O- or S-substituted tetrahydronaphthalene derivatives having retinoid and/or retinoid antagonist-like biological activity

ABSTRACT

Compounds of the formula  
                 
 
     where the symbols have the meaning described in the application, have retinoid-like or retinoid antagonist-like biological activity.

1. FIELD OF THE INVENTION

[0001] The present invention relates to novel compounds having retinoidand/or retinoid antagonist-like biological activity. More specifically,the present invention relates to O- or S-substitutedtetrahydronaphthalene derivatives which bind to retinoid receptors andhave retinoid-like or retinoid antagonist-like biological activity.

2. BACKGROUND ART

[0002] Compounds which have retinoid-like activity are well known in theart, and are described in numerous United States and other patents andin scientific publications. It is generally known and accepted in theart that retinoid-like activity is useful for treating animals of themammalian species, including humans, for curing or alleviating thesymptoms and conditions of numerous diseases and conditions. In otherwords, it is generally accepted in the art that pharmaceuticalcompositions having a retinoid-like compound or compounds as the activeingredient are useful as regulators of cell proliferation anddifferentiation, and particularly as agents for treating skin-relateddiseases, including, actinic keratoses, arsenic keratoses, inflammatoryand non-inflammatory acne, psoriasis, ichthyoses and otherkeratinization and hyperproliferative disorders of the skin, eczema,atopic dermatitis, Darriers disease, lichen planus, prevention andreversal of glucocorticoid damage (steroid atrophy), as a topicalanti-microbial, as skin anti-pigmentation agents and to treat andreverse the effects of age and photo damage to the skin. Retinoidcompounds are also useful for the prevention and treatment of cancerousand precancerous conditions, including, premalignant and malignanthyperproliferative diseases such as cancers of the breast, skin,prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung,larynx, oral cavity, blood and lymphatic system, metaplasias,dysplasias, neoplasias, leukoplakias and papillomas of the mucousmembranes and in the treatment of Kaposi's sarcoma. In addition,retinoid compounds can be used as agents to treat diseases of the eye,including, without limitation, proliferative vitreoretinopathy (PVR),retinal detachment, dry eye and other corneopathies, as well as in thetreatment and prevention of various cardiovascular diseases, including,without limitation, diseases associated with lipid metabolism such asdyslipidemias, prevention of post-angioplasty restenosis and as an agentto increase the level of circulating tissue plasminogen activator (TPA).Other uses for retinoid compounds include the prevention and treatmentof conditions and diseases associated with human papilloma virus (EPV),including warts and genital warts, various inflammatory diseases such aspulmonary fibrosis, ileitis, colitis and Krohn's disease,neurodegenerative diseases such as Alzheimer's disease, Parkinson'sdisease and stroke, improper pituitary function, including insufficientproduction of growth hormone, modulation of apoptosis, including boththe induction of apoptosis and inhibition of T-Cell activated apoptosis,restoration of hair growth, including combination therapies with thepresent compounds and other agents such as Minoxidil^(R), diseasesassociated with the immune system, including use of the presentcompounds as immunosuppressants and immunostimulants, modulation oforgan transplant rejection and facilitation of wound healing, includingmodulation of chelosis.

[0003] U.S. Pat. Nos. 4,740,519 (Shroot et al.), 4,826,969 (Maignan etal.), 4,326,055 (Loeliger et al.), 5,130,335 (Chandraratna et al.),5,037,825 (Klaus et al.), 5,231,113 (Chandraratna et al.), 5,324,840(Chandraratna), 5,344,959 (Chandraratna), 5,130,335 (Chandraratna etal.), Published European Patent Application Nos. 0 176 034 A (Wuest etal.), 0 350 846 A (Klaus et al.), 0 176 032 A (Frickel et al.), 0 176033 A (Frickel et al.), 0 253 302 A (Klaus et al). 0 303 915 A (Bryce etal.), UK Patent Application GB 2190378 A (Klaus et al.), German PatentApplication Nos. DE 3715955 A1 (Klaus et al.). DE 3602473 A1 (Wuest etal., and the articles J. Amer. Acad. Derm. 15: 756-764 (1986) (Sporn etal.), Chem. Pharm. Bull. 33: 404-407 (1985) (Shudo et al.), J. Med Chem.1988 31, 2182-2192 (Kagechika et al.), Chemistry and Biology ofSynthetic Retinoids CRC Press Inc. 1990 p 334-335, 354 (Dawson et al.),describe or relate to compounds which include a tetrahydronaphthylmoiety and have retinoid-like or related biological activity. U.S. Pat.No. 4,391,731 (Boller et al.) describes tetrahydronaphthalenederivatives which are useful in liquid crystal compositions.

[0004] Published European Patent application Nos. 0 661 259 A1 and 0 661261 A1 (Bristol-Myers Squibb) describe further dihydronaphthalene andnaphthalene derivatives which are said in the disclosures to haveretinoid-like biological activity.

[0005] U.S. Pat. Nos. 4,980,369, 5,006,550, 5,015,658, 5,045,551,5,089,509, 5,134,159, 5,162,546, 5,234,926, 5,248,777, 5,264,578,5,272,156, 5,278,318, 5,324,744, 5,346,895, 5,346,915, 5,348,972,5,348,975, 5,380,877, 5,399,561, 5,407,937, (assigned to the sameassignee as the present application) and patents and publications citedtherein, describe or relate to chroman, thiochroman and1,2,3,4-tetrahydroquinoline derivatives which have retinoid-likebiological activity. Still further, several co-pending applications andrecently issued patents which are assigned to the assignee of thepresent application, are directed to further compounds havingretinoid-like activity.

[0006] Although pharmaceutical compositions containing retinoids havewell established utility (as is demonstrated by the foregoing citationof patents and publications from the voluminous literature devoted tothis subject) retinoids also cause a number of undesired side effects attherapeutic dose levels, including headache, teratogenesis,mucocutaneous toxicity, musculoskeletal toxicity, dyslipidemias, skinirritation, headache and hepatotoxicity. These side effects limit theacceptability and utility of retinoids for treating disease.

[0007] It is now general knowledge in the art that two main types ofretinoid receptors exist in mammals (and other organisms). The two maintypes or families of receptors respectively designated the RARs andRXRs. Within each type there are subtypes; in the RAR family thesubtypes are designated RAR_(α), RAR_(β) and RAR_(γ), in RXR thesubtypes are: RXR_(α), RXB_(β) and RXR_(γ). It has also been establishedin the art that the distribution of the two main retinoid receptortypes, and of the several sub-types is not uniform in the varioustissues and organs of mammalian organisms. Moreover, it is generallyaccepted in the art that many unwanted side effects of retinoids aremediated by one or more of the RAR receptor subtypes. Accordingly, amongcompounds having agonist-like activity at retinoid receptors,specificity or selectivity for one of the main types or families, andeven specificity or selectivity for one or more subtypes within a familyof receptors, is considered a desirable pharmacological property. Somecompounds bind to one or more RAR receptor subtypes, but do not triggerthe response which is triggered by agonists of the same receptors. Acompound that binds to a biological receptor but does not trigger anagonist-like response is usually termed an antagonist. Accordingly, the“effect” of compounds on retinoid receptors may fall in the range ofhaving no effect at all, (inactive compound, neither agonist norantagonist), the compound may elicit an agonist-like response on allreceptor subtypes (pan-agonist), or a compound may be a partial agonistand/or partial antagonist of certain receptor subtypes if the compoundbinds to but does not activate certain receptor subtype or subtypes butelicits an agonist-like response in other receptor subtype or subtypes.A pan antagonist is a compound that binds to all known retinoidreceptors but does not elicit an agonist-like response in any of thereceptors.

[0008] It has been recently discovered and described in a pendingapplication assigned to the same assignee as the present applicationthat retinoid antagonist-like activity of a compound is also a usefulproperty, in that such antagonist compounds can be utilized to blockcertain undesired side effects of retinoids, to serve as antidotes toretinoid overdose or poisoning, and may lend themselves to otherpharmaceutical applications as well. More particularly, regarding thepublished scientific and patent literature in this field, published PCTapplication WO 94/14777 describes certain heterocyclic carboylic acidderivatives which bind to RAR retinoid receptors and are said in theapplication to be useful for treatment of certain diseases orconditions, such as acne, psoriasis, rheumatoid arthritis and viralinfections. A similar disclosure is made in the article by Yoshimura etal. J. Med. Chem. 1995, 38, 3163-3173. Kaneko et al. Med. Chem Res.(1991) 1:220-225; Apfel et al. Proc. Natl. Acad. Sci. USA Vol 89 pp7129-7133 Augusty 1992 Cell Biology; Eckhardt et al. Toxicology Letters,70 (1994) 299-308; Keidel et al. Molecular and Cellular Biology, Vol 14,No. 1, January 1994, p 287-298; and Eyrofles et al. J. Med. Chem. 1994,37, 1508-1517 describe compounds which have antagonist like activity atone or more of the RAR retinoid subtypes.

SUMMARY OF THE INVENTION

[0009] Among the compounds of Formulas 1 through 6, the presentinvention covers the compounds of Formula 1. Compounds of the remainingformulas are disclosed here inasmuch as the methods of their synthesispertains to the best modes of the presently contemplated syntheticroutes leading to the compounds of Formula 1. Thus the present inventionpertains to compounds of Formula 1

Formula 1

[0010] wherein X₁ is [C(R₁)₂]_(n) where R₁ is independently H or alkylof 1 to 6 carbons, and n is an integer between 0 and 2;

[0011] X₂ is S or O;

[0012] Z is —N═N—,

[0013] —N(O)═N—,

[0014] —N═N(O)—,

[0015] —N═CR₁—,

[0016] —CR₁═N,

[0017] —(CR₁═CR₁)_(n′)— where n′ is an integer having the value 0-5,

[0018] —CO—NR—,

[0019] —CS—NR₁—,

[0020] —NR₁—CO,

[0021] —NR₁—CS,

[0022] —COO—,

[0023] —OCO—;

[0024] —CSO—;

[0025] —OCS—;

[0026] —CO—CR₁═CR₁—;

[0027] R₂ is hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF₃,fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6carbons, or alkylthio of 1 to 6 carbons;

[0028] R₃ is hydrogen, lower alkyl of 1 to 6 carbons or F;

[0029] m is an integer having the value of 0-3;

[0030] o is an integer having the value of 0-4;

[0031] R₄ is hydrogen, alkyl of 1 to 10 carbons, alkenyl of 2 to 10carbons and having 1 to 3 double bonds, alkynyl having 2 to 10 carbonsand 1 to 3 triple bonds, carbocyclic aryl selected from the groupconsisting of phenyl, C₁-C₁₀-alkylphenyl, naphthyl,C₁-C₁₀-alkyl-naphtyl, phenyl-C₁-C₁₀-alkyl, napthyl-C₁-C₁₀ alkyl; CN, or(CH₂)_(p)CO₂R₈ where p is an integer between 0 to 10;

[0032] R₅ is hydrogen, alkyl of 1 to 10 carbons, fluoro-substitutedalkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3double bonds, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds,carbocyclic aryl selected from the group consisting of phenyl,C₁-C₁₀-alkylphenyl, naphthyl, C₁-C₁₀-alkylnaphthyl, phenyl-C₁-C₁₀-alkyl,napthyl-C₁-C₁₀-alkyl; Si(C₁₋₆aryl)₃, COR₁₄, camphanoyl,C(R₁₅)(R₁₆)X₂R₁₇;

[0033] Y is a phenyl or naphthyl group, or heteroaryl selected from agroup consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyland heteroaryl groups being optionally substituted with one or two R₂groups, or

[0034] when Z is —(CR₁═CR₁)_(n′)— and n′ is 3, 4 or 5 then Y representsa direct valence bond between said (CR₁═CR₂)_(n′) group and B;

[0035] A is (CH₂)_(q) where q is 0-5, lower branched chain alkyl having3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbonsand 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triplebonds;

[0036] B is hydrogen, COOH or a pharmaceutically acceptable saltthereof, COOR₈, CONR₉R₁₀, —CH₂OH, CH₂OR₁₁, CH₂OCOR₁₁, CHO, CH(OR₁₂)₂,CHOR₁₃O, —COR₇, CR₇(OR₁₂)₂, CR₇OR₁₃O, or Si(C₁₋₆alkyl)₃, where R₇ is analkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R₇ is analkyl group of 1 to 10 carbons or (trimethylsilyl)alkyl where the alkylgroup has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, orR₈ is phenyl or lower alkylphenyl, R₉ and R₁₀ independently arehydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of5-10 carbons, or phenyl or lower alkylphenyl, R₁₁ is lower alkyl, phenylor lower alkylphenyl, R₁₂ is lower alkyl, and R₁₃ is divalent alkylradical of 2-5 carbons;

[0037] R₁₄ is hydrogen, alkyl of 1 to 10 carbons, alkenyl of 2 to 10carbons and having 1 to 3 double bonds, alkyl having 2 to 10 carbons and1 to 3 triple bonds, carbocyclic aryl selected from the group consistingof phenyl, C₁-C₁₀-alkylphenyl, naphthyl, C₁-C₁₀-alkylnaphthyl,phenyl-C₁-C₁₀ alkyl, napthyl-C₁-C₁₀alkyl, and

[0038] R₁₅ and R₁₆ are hydrogen or lower alkyl of 1 to 6 carbons, R₁₇ islower alkyl of 1 to 6 carbons, or R₁₆ and R₁₇ jointly form a ring havinga total of 4 to 5 carbons and the X₂ heteroatom;

[0039] compounds of Formula 2

[0040] wherein X₁ is [C(R₁)₂]_(n) where R₁ is independently H or alkylof 1 to 6 carbons, and n is an integer between 0 and 2;

[0041] X₂ is S or O;

[0042] Z is —N═N—,

[0043] —N(O)═N—,

[0044] —N═N(O)—,

[0045] —N═CR₁—,

[0046] —CR₁═N,

[0047] —(CR₁═CR₁)_(n′) where n′ is an integer having the value 0-5,

[0048] —CO—NR₁—,

[0049] —CS—NR₁—,

[0050] —NR₁—CO,

[0051] —NR₁—CS,

[0052] —COO—,

[0053] —OCO—;

[0054] —CSO—;

[0055] —OCS—;

[0056] is —CO—CR₁═CR₁—;

[0057] R is hydrogen, lower alkyl of 1 to 6 carbons, F, a, Br, I, CF₃,fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6carbons, or alkylthio of 1 to 6 carbons;

[0058] R₃ is hydrogen, lower alkyl of 1 to 6 carbons or F;

[0059] m is an integer having the value of 0-3;

[0060] o is an integer having the value of 0-4;

[0061] Y is a phenyl or naphthyl group, or heteroaryl selected from agroup consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyland heteroaryl groups being optionally substituted with one or two R₂groups, or

[0062] when Z is —(CR₁═CR₁)_(n′)— and n′ is 3, 4 or 5 then Y representsa direct valence bond between said (CR₂═CR₂)_(n′) group and B;

[0063] A is (CH)_(q) where q is 0-5, lower branched chain alkyl having3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbonsand 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triplebonds;

[0064] B is hydrogen, COOH or a pharmaceutically acceptable saltthereof, COOR₈, CONR₉R₁₀, —COH, CH₂OR₁₁, CH₂OCOR₁₁, CHO, CH(OR₁₂)₂,CHOR₁₃O, —COR₇, CR₇(OR₁₂)₂, CR₇OR₁₃O, or Si(C₁₋₆alkyl)₃, where R₇ is analkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R₈ is analkyl group of 1 to 10 carbons or (trimethylsilyl)alkyl where the alkylgroup has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, orR₈ is phenyl or lower alkylphenyl, R₉ and R₁₀ independently arehydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of5-10 carbons, or phenyl or lower alkylphenyl, R₁₁ is lower alkyl, phenylor lower alklylphenyl, R₁₂ is lower alkyl, and R₁₃ is divalent alkylradical of 2-5 carbons, and

[0065] R₁₈ is alkyl of 1 to 10 carbons, fluoro-substituted alkyl of 1 to10 carbons, or the two R₁₈ groups jointly form a ring having a total of3 to 6 carbons, or the two X₂R₁₈ groups jointly symbolize an oxo (═O) ora thio (═S) function, or each of the two X₂R₁₈ groups is H;

[0066] compounds of Formula 3

[0067] wherein X₁ is [C(R₁)_(n)] where R, is independently H or alkyl of1 to 6 carbons, and n is an integer between 0 and 2;

[0068] Z is —N═N—,

[0069] —N(O)═N;

[0070] —N═N(O)—,

[0071] —N═CR₁—,

[0072] —CR₁═N,

[0073] —(CR₁═CR₁)_(n′)— where n′ is an integer having the value 0-5,

[0074] —CO—NR₁—,

[0075] —CS—NR₁—,

[0076] —NR₁—CO,

[0077] —NR₁—CS,

[0078] —COO—,

[0079] —OCO—;

[0080] —CSO—;

[0081] —OCS—;

[0082] —CO—CR₁═CR₁—;

[0083] R₂ is hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF₃,fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6carbons, or alkylthio of 1 to 6-carbons;

[0084] R₃ is hydrogen, lower alkyl of 1 to 6 carbons or F;

[0085] m is an integer having the value of 0-3;

[0086] o is an integer having the value of 0-4;

[0087] Y is a phenyl or naphthyl group, or heteroaryl selected from agroup consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyland heteroaryl groups being optionally substituted with one or two R₂groups, or when Z is —(CR₁═CR₁)_(n′)— and n′ is 3, 4 or 5 then Yrepresents a direct valence bond between said (CR₂═CR₂)_(n′) group andB;

[0088] A is (CH₂)_(q) where q is 0-5, lower branched chain alkyl having3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbonsand 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triplebonds;

[0089] B is hydrogen, COOH or a pharmaceutically acceptable saltthereof, COOR₈, CONR₉R₁₀, —CH₂OH, CH₂OR₁₁, CH₂OCOR₁₁, CHO, CH(OR₁₂)₂,CHOR₁₃O, —COR₇, CR₇(OR₁₂)₂, CR₇OR₁₃O, or Si(C₁₋₆alkyl)₃, where R₇ is analkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R₈ is analkyl group of 1 to 10 carbons or (trimethylsilyl)alkyl where the alkylgroup has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, orR₈ is phenyl or lower alkylphenyl, R₉ and R₁₀ independently arehydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of5-10 carbons, or phenyl or lower alkylphenyl, R₁₁ is lower alkyl, phenylor lower alkylphenyl, R₁₂ is lower alkyl, and R₁₃ is divalent alkylradical of 2-5 carbons, and

[0090] R₁₉ is independently hydrogen, alkyl of 1 to 10 carbons, 19fluoro-substituted alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbonsand having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to3 triple bonds, carbocyclic aryl selected from the group consisting ofphenyl, C₁-C₁₀-alkylphenyl, naphthyl, C₁-C₁₀-alkylnaphthyl,phenyl-C₁-C₁₀alkyl, naphthyl-C₁-C₁₀alkyl; heteroaryl selected from thegroup consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyland heteroaryl groups being optionally substituted with one or two Rgroups, further R₁₉ is independently CN, CHO, CH(OR₁₂)₂, CHOR₁₃O,(CH₂)_(p)CO₂R₈, (CH₂)_(p)CH₂OH, (CH₂)_(p)CH₂OR₁₁, (CH₂)_(p)CH₂OCOR₁₁,where p is an integer between 0 to 10, or the two R₁₉ groups jointlyrepresent 3 to 8 methylene groups which together with the alkylidenecarbon complete a ring, the ring optionally containing 1 to 2 doublebonds and the ring being optionally substituted with 1 or 2 R₂ groups;

[0091] compounds of Formula 4

[0092] wherein X₁ is [C(R₁)₂]_(n) where R₁ is independently H or alkylof 1 to 6 carbons, and n is an integer between 0 and 2;

[0093] Z is —N═N—,

[0094] —N(O)═N—,

[0095] —N═N(O)—,

[0096] —N═CR₁—,

[0097] —(CR₁═CR₁)_(n′) where n′ is an integer having the value 0-5,

[0098] —CO—NR₁—,

[0099] —CS—NR₁—,

[0100] —NR₁—CO,

[0101] —NR₁—CS,

[0102] —COO—,

[0103] —OCO—;

[0104] —CSO—;

[0105] —OCS—;

[0106] —CO—CR₁═CR₁—;

[0107] R₁ is hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF₃,fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6carbons, or alkylthio of 1 to 6 carbons;

[0108] R₃ is hydrogen, lower alkyl of 1 to 6 carbons or F;

[0109] m is an integer having the value of 0-3;

[0110] o is an integer having the value of 0-4;

[0111] Y is a phenyl or naphthyl group, or heteroaryl selected from agroup consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyland heteroaryl groups being optionally substituted with one or two R₂groups, or

[0112] when Z is —(CR₁═CR₁)_(n′)— and n′ is 3, 4 or 5 then Y representsa direct valence bond between said (CR₂═CR₂)_(n′) group and B;

[0113] A is (CH₂)_(q) where q is 0-5, lower branched chain alkyl having3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbonsand 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triplebonds;

[0114] B is hydrogen, COOH or a pharmaceutically acceptable, saltthereof, COOR₈, CONR₉R₁₀, —CH₂OH, CH₂OR₁₁, CH₂OCOR₁₁, CHO, CH(OR₁₂)₂,CHOR₁₃O, —COR₇, CR₇(OR₁₂)₂, CR₇OR₁₃O, or Si(C₁₋₆alkyl)₃, where R₇ is analkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R₈ is analkyl group of 1 to 10 carbons or (trimethylsilyl)alkyl where the alkylgroup has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, orR₈ is phenyl or lower alkylphenyl, R₉ and R₁₀ independently arehydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of5-10 carbons, or phenyl or lower alkylphenyl, R₁₁ is lower alkyl, phenylor lower alkylphenyl, R₁₂ is lower alkyl, and R₁₃ is divalent alkylradical of 2-5 carbons, and

[0115] Z₂ is OR₁ or OR₁₈ where R₁₈ is is phenyl, benzyl, lower alkyl orlower alkoxy substituted phenyl, or Z₂ is OSi(R₁)₃, OCOR₁₄,OC(R₁₅)(R₁₆)X₂R₁₇, N(R₁₄)₂, NHCSN₁₄)₂, NHCSN(R₁₄)₂, where X₂ is O or S;R₁₄ is hydrogen, alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbonsand having 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to3 triple bonds, carbocyclic aryl selected from the group consisting ofphenyl, C₁-C₁₀-alkylphenyl, naphthyl, C₁-C₁₀-alkylnaphthyl,phenyl-C₁-C₁₀alkyl, naphthyl-C₁-C₁₀alkyl; R₁, and R₁₆ are hydrogen orlower alkyl of 1 to 6 carbons, R₁₇ is lower alkyl of 1 to 6 carbons, orR₁₆ and R₁₇ jointly form a ring having a total of 4 to 5 carbons and theX₂ heteroatom;

[0116] compounds of Formula 5

[0117] wherein X₁ is [C(R₁)₂]_(n) where R₁ is independently H or alkylof 1 to 6 carbons, and n is an integer between 0 and 2;

[0118] Z is —N═N—,

[0119] —N(O)═N—,

[0120] —N═N(O)—,

[0121] —N═CR₁—,

[0122] —CR═N,

[0123] —(CR₁═CR₁)_(n′)— where n′ is an integer having the value 0-5,

[0124] —CO—NR₁—,

[0125] —CS—NR₁—,

[0126] —NR₁—CO,

[0127] —NR₁—CS,

[0128] —COO—,

[0129] —OCO—;

[0130] —CSO—;

[0131] —OCS—;

[0132] —CO—CR₁═CR₁—;

[0133] R₂ is hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF₃,fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6carbons, or alkylthio of 1 to 6 carbons;

[0134] R₃ is hydrogen, lower alkyl of 1 to 6 carbons or F;

[0135] is m is an integer having the value of 0-3;

[0136] o is an integer having the value of 0-3;

[0137] Y is a phenyl or naphthyl group, or heteroaryl selected from agroup consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyland heteroaryl groups being optionally substituted with one or two R₂groups, or

[0138] when Z is —(CR₁═CR₁)_(n′)— and n′ is 3, 4 or 5 then Y representsa direct valence bond between said (CR₂═CR₂)_(n′) group and B;

[0139] A is (CH₂)_(q) where q is 0-5, lower branched chain alkyl having3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbonsand 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triplebonds;

[0140] B is hydrogen, COOH or a pharmaceutically acceptable saltthereof, COOR₈, CONR₉R₁₀, —CH₂OH, CH₂OR₁₁, CH₂OCOR₁₁, CHO, CH(OR₁₂))₂,CHOR₁₃O, —COR₇, CR₇(OR₁₂)₂, CR₇OR₁₃O, or Si(C₁₋₆alkyl)₃, where R₇ is analkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R₈ is analkyl group of 1 to 10 carbons or (trimethylsilyl)alkyl where the alkylgroup has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, orR₈ is phenyl or lower alkylphenyl, R₉ and R₁₀ independently arehydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of5-10 carbons, or phenyl or lower alkylphenyl, R₁₁ is lower alkyl, phenylor lower alkylphenyl, R₁₂ is lower alkyl, and R₁₃ is divalent alkylradical of 2-5 carbons;

[0141] X₂ is O, S, SO or SO₂, and

[0142] R₂₀ is Si(C₁₋₆alkyl)₃, R₁₄, COR₁₄, SO₂R₂₁, where R₁₄ is hydrogen,alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3double bond, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds,carbocyclic aryl selected from the group consisting of phenyl,C₁-C₁₀-alkylphenyl, naphthyl, C₁-C₁₀-alkylnaphthyl, phenyl-C₁-C₁₀alkyl,napthyl-C₁-C₁₀alkyl, or R₂₀ is hydroxyalkyl, aminoalkyl or thioalkylhaving 1 to 10 carbons; and R₂₁ is alkyl of 1 to 10 carbons, fluoroalkylof 1 to 10 carbons, or carbocyclic aryl selected from the groupconsisting of phenyl, C₁-C₁₀-alkylphenyl and phenyl-C₁-C₁₀alkyl, and

[0143] compounds of Formula 6

[0144] wherein X₁ is [C(R₁)₂]_(n) where R₁ is independently H or alkylof 1 to 6 carbons, and n is an integer between 0 and 2;

[0145] Z is —N═N—,

[0146] —N(O)═N—,

[0147] —N═N(O)—,

[0148] —N═CR₁—,

[0149] —CR₁═N,

[0150] —(CR₁═CR₁)_(n′)— where n′ is an integer having the value 0-5,

[0151] —CO—NR₁—,

[0152] —CS—NR₁—,

[0153] —NR₁—CO,

[0154] —NR₁—CS,

[0155] —COO—,

[0156] —OCO—;

[0157] —CSO—;

[0158] —OCS—;

[0159] —CO—CR₁═CR₁—;

[0160] R₂ is hydrogen, lower alkyl of 1 to 6 carbons, F, Cl, Br, I, CF₃,fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6carbons, or alkylthio of 1 to 6 carbons;

[0161] R₃ is hydrogen, lower alkyl of 1 to 6 carbons or F;

[0162] m is an integer having the value of 0-3;

[0163] o is an integer having the value of 0-3;

[0164] Y is a phenyl or naphthyl group, or heteroaryl selected from agroup consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyland heteroaryl groups being optionally substituted with one or two R₂groups, or

[0165] when Z is —(CR₁═CR₁)_(n′)— and n′ is 3, 4 or 5 then Y representsa direct valence bond between said (CR₂═CR₂)_(n′) group and B;

[0166] A is (CH₂)_(q) where q is 0-5, lower branched chain alkyl having3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbonsand 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triplebonds;

[0167] B is hydrogen, COOH or a pharmaceutically acceptable saltthereof, COOR₈, CONR₉R₁₀, —CH₂OH, CH₂OR₁₁, CH₂OCOR₁₁, CHO, CH(OR₁₂)₂,CHOR₁₃O, —COR₇, CR₇(OR₁₂)₂, CR₇OR₁₃O, or Si(C₁-C₆alkyl)₃, where R₇ is analkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R₈ is analkyl group of 1 to 10 carbons or (trimethylsilyl)alkyl where the alkylgroup has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, orR₈ is phenyl or lower alkylphenyl, R₉ and R₁₀ independently arehydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of5-10 carbons, or phenyl or lower alkylphenyl, R₁₁ is lower alkyl, phenylor lower alkylphenyl, R₁₂ is lower alkyl, and R₁₃ is divalent alkylradical of 2-5 carbons;, and

[0168] R₁₄ is (R₁₅)_(r)-substituted alkyl of 1-6 carbons,(R₁₅)_(r)-substituted alkenyl of 1-6 carbons and 1 or 2 double bonds,(R₁₅)_(r)-substituted alkynyl of 1-6 carbons and 1 or 2 triple bonds,(R₁₅)_(r)-phenyl, (R₁₅)_(r)-naphthyl, or (R₁₅)_(r)-heteroaryl where theheteroaryl group has 1 to 3 heteroatoms selected from the groupconsisting of O, S and N, r is an integer having the values of 0-5, and

[0169] R₁₅ is independently H, F, Cl, Br, I, NO₂, N(R₈)₂, N(R)COR₈,NR₈CON(R₈)₂, OH, OCOR₈, OR₈, CN, COOH, COOR₈ an alkyl group having 1 to10 carbons, fluoro substituted alkyl group having 1 to 10 carbons, analkenyl group having 1 to 10 carbons and 1 to 3 double bonds, alkynylgroup having 1 to 10 carbons and 1 to 3 triple bonds, or a(trialkyl)silyl or (trialkyl)silyloxy group where the alkyl groupsindependently have 1 to 6 carbons.

[0170] In a second aspect, this invention relates to the use of thecompounds of Formula 1 through Formula 6 for the treatment ofskin-related diseases, including, without limitation, actinic keratoses,arsenic keratoses, inflammatory and non-inflammatory acne, psoriasis,ichthyoses and other keratinization and hyperproliferative disorders ofthe skin, eczema, atopic dermatitis, Darriers disease, lichen planus,prevention and reversal of glucocorticoid damage (steroid atrophy), as atopical anti-microbial, as skin anti-pigmentation agents and to treatand reverse the effects of age and photo damage to the skin. Thecompounds are also useful for the prevention and treatment of cancerousand precancerous conditions, including, premalignant and malignanthyperproliferative diseases such as cancers of the breast, skin,prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung,larynx, oral cavity, blood and lymphatic system, metaplasias,dysplasias, neoplasias, leukoplakias and papillomas of the mucousmembranes and in the treatment of Kaposi's sarcoma. In addition, thepresent compounds can be used as agents to treat diseases of the eye,including, without limitation, proliferative vitreoretinopathy (PVR),retinal detachment, dry eye and other corneopathies, as well as in thetreatment and prevention of various cardiovascular diseases, including,without limitation, diseases associated with lipid metabolism such asdyslipidemias, prevention of post-angioplasty restenosis and as an agentto increase the level of circulating tissue plasminogen activator (IPA).Other uses for the compounds of the present invention include theprevention and treatment of conditions and diseases associated withHuman papilloma virus (HPV), including warts and genital warts, variousinflammatory diseases such as pulmonary fibrosis, ileitis, colitis andKrohn's disease, neurodegenerative diseases such as Alzheimer's disease,Parkinson's disease and stroke, improper pituitary function, includinginsufficient production of growth hormone, modulation of apoptosis,including both the induction of apoptosis and inhibition of T-Cellactivated apoptosis, restoration of hair growth, including combinationtherapies with the present compounds and other agents such asMinoxidil^(R), diseases associated with the immune system, including useof the present compounds as immunosuppressants and immunostimulants,modulation of organ transplant rejection and facilitation of woundhealing, including modulation of chelosis.

[0171] Alternatively, those compounds of the invention which act asantagonists of one or more retinoid receptor subtypes are useful toprevent certain undesired side effects of retinoids which areadministered for the treatment or prevention of certain diseases orconditions. For this purpose the retinoid antagonist compounds of theinvention may be co-administered with retinoids. The compounds of thepresent invention are also useful in the treatment of acute or chronictoxicity resulting from overdose or poisoning by retinoid drugs orVitamin A.

[0172] This invention also relates to a pharmaceutical formulationcomprising a compound of Formula 1 through Formula 6 in admixture with apharmaceutically acceptable excipient, said formulation being adaptedfor administration to a mammal, including a human being, to treat oralleviate the conditions which were described above as treatable byretinoids, to be co-administered with retinoids to eliminate or reduceside effects of retinoids, or to treat retinoid or Vitamin A overdose orpoisoning.

Biological Activity, Modes of Administration Assay of Retinoid-like orRetinoid Antagonist-like Biological Activity

[0173] A classic measure of retinoic acid activity involves measuringthe effects of retinoic acid on ornithine decarboxylase. The originalwork on the correlation between retinoic acid and decrease in cellproliferation was done by Verma & Boutwell, Cancer Research, 1977,37,219&2201. That reference discloses that ornithine decarboxylase (ODC)activity increased precedent to polyamine biosynthesis. It has beenestablished elsewhere that increases in polyamine synthesis can becorrelated or associated with cellular proliferation. Thus, if ODCactivity could be inhibited, cell hyperproliferation could be modulated.Although all cases for ODC activity increases are unknown, it is knownthat 12-0-tetradecanoylphorbol-13-acetate (TBA) induces ODC activity.Retinoic acid inhibits this induction of ODC activity by TPA. An assayessentially following the procedure set out in Cancer Research:1662-1670,1975 may be used to demonstrate inhibition of TPA induction ofODC by compounds of this invention. Activity of exemplary compounds ofthe present invention in the above-described ODC assay is disclosed inTable 1 which provides the IC₆₀ concentration for the respectiveexemplary compound. (“IC₆₀” is that concentration of the test compoundwhich causes 60% inhibition in the ODC assay. By analogy, “IC₈₀, forexample, is that concentration of the test compound which causes 80%inhibition in the ODC assay.) TABLE 1 ODC Assay Compound No. IC₆₀(nmols)A5 10.3 D3 8.4 C22b 10 E24 8.3 A16 4.3 (IC₈₀) C14 4 E79 5.3 D34 4.3(IC₈₀) C15 14.5 E15 24.7 A27 0.7 E16 88.4 A23 43.7 A2 27 E72b 18 E56a3.1 D6 1.9

[0174] Other assays described below, measure the ability of thecompounds of the present invention to bind to, and/or activate variousretinoid receptor subtypes. When in these assays a compound binds to agiven receptor subtype and activates the transcription of a reportergene through that subtype, then the compound is considered an agonist ofthat receptor subtype. Conversely, a compound is considered anantagonist of a given receptor subtype if in the below describedco-tranfection assays the compound does not cause significanttranscriptional activation of the receptor regulated reporter gene, butnevertheless binds to the receptor with a K_(d) value of less thanapproximately 1 micromolar. In the below described assays the ability ofthe compounds to bind to RAR_(α), RAR_(β), RAR_(γ), RXR_(α), RXR_(β) andRXR_(Γ) receptors, and the ability or inability of the compounds toactivate transcription of a reporter gene through these receptorsubtypes can be tested.

[0175] Specifically, a chimeric receptor transactivation assay whichtests for agonist-like activity in the RAR_(α), RAR_(β), RAR_(γ),RXR_(α) receptor subtypes, and which is based on work published byFeigner P. L. and Holm M. (1989) Focus, 11 2 is described in detail inU.S. Pat. No. 5,455,265 the specification of which is hereby expresslyincorporated by reference.

[0176] A hoboreceptor transactivation assay and a ligand binding assaywhich measure the antagonist/agonist like activity of the compounds ofthe invention, or their ability to bind to the several retinoid receptorsubtypes, respectively, are described in published PCT Application No.WO WO93/11755 (particularly on pages 30-33 and 37-41) published on Jun.24, 1993, the specification of which is also incorporated herein byreference. A description of the holoreceptor transactivation assay isalso provided below.

[0177] Holoreceptor Transactivation Assay

[0178] CV1 cells (5,000 cells/well) were transfected with an RARreporter plasmid MTV-TREp-LUC (50 ng) along with one of the RARexpression vectors (10 ng) in an automated 96-well format by the calciumphosphate procedure of Hegman et al. Cell 68, 397-406, (1992). ForRXR_(α) and RXR_(γ) transactivation assays, an RXR-responsive reporterplasmid CRBPII-tk-LUC (50 ng) along with the appropriate RXR expressionvectors (10 ng) was used substantially as described by Heyman et al.above, and Allegretto et al. J. Biol. Chem. 268, 26625-26633. ForRXR_(β) transactivation assays, an RXR-responsive reporter plasmidCPRE-tk-LUC (50 mg) along with RXR₈ expression vector (10 mg) was usedas described in above. These reporters contain DRI elements from humanCRBPII and certain DRI elements from promoter, respectively. (seeMangelsdorf et al. The Retinoids: Biology, Chemistry and Medicine, pp319-349, Raven Press Ltd., New York and Hevman et al., cited above) (1,8). A β-galactosidase (50 ng) expression vector was used as an internalcontrol in the transfections to normalize for variations in transfectionefficiency. The cells were transfected in triplicate for 6 hours,followed by incubation with retinoids for 36 hours, and the extractswere assayed for luciferase and β-galactosidase activities. The detailedexperimental procedure for holoreceptor transactivations has beendescribed in Heyman et al. above, and Allegretto et al. cited above. Theresults obtained in this assay are expressed in EC₅₀ numbers, as theyare also in the chimeric receptor transactivation assay. The Heyman etal. Cell 68, 397-406, Allegretto et al. J. Biol. Chem. 268, 26625-26633,and Mangelsdorf et al. The Retinoids: Biology, Chemistry and Medicine,pp 319-349, Raven Press Ltd., New York, are expressly incorporatedherein by reference. The results of ligand binding assay are expressedin K_(d) numbers. (See Cheng et al. Biochemical Pharmacology Vol. 22 pp3099-3108, expressly incorporated herein by reference.)

[0179] Table 2 shows the results of the ligand binding assay for certainexemplary compounds of the invention for the receptor subtypes in theRAR group. TABLE 2 Ligand Binding Assay Compound K_(d) (nanomolar, nM)No. RARα RARβ RARγ A6 125 36 127 D4 1000 132 363 C25 19 12 42 E27 551535 >1000 A18 538 193 162 E80 394 531 901 D34 235 200 530 E14 36 35 455A28 4 3 42 E17 192 378 >1000 A24 283 92 259 A2a 150 219 421 E67 77 302375 D7 >1000 226 >1000

[0180] Modes of Administration

[0181] The compounds of this invention may be administered systemicallyor topically, depending on such considerations as the condition to betreated, need for site-specific treatment, quantity of drug to beadministered, and numerous other considerations.

[0182] In the treatment of dermatoses, it will generally be preferred toadminister the drug topically, though in certain cases such as treatmentof severe cystic acne or psoriasis, oral administration may also beused. Any common topical formulation such as a solution, suspension,gel, ointment, or salve and the like may be used. Preparation of suchtopical formulations are well described in the art of pharmaceuticalformulations as exemplified, for example, by Remington's PharmaceuticalScience, Edition 17, Mack Publishing Company, Easton, Pennsylvania. Fortopical application, these compounds could also be administered as apowder or spray, particularly in aerosol form. If the drug is to beadministered systemically, it may be confected as a powder, pill, tabletor the like or as a syrup or elixir suitable for oral administration.For intravenous or intraperitoneal administration, the compound will beprepared as a solution or suspension capable of being administered byinjection. In certain cases, it may be useful to formulate thesecompounds by injection. In certain cases, it may be useful to formulatethese compounds in suppository form or as extended release formulationfor deposit under the skin or intramuscular injection.

[0183] Other medicaments can be added to such topical formulation forsuch secondary purposes as treating skin dryness; providing protectionagainst light; other medications for treating dermatoses; medicamentsfor preventing infection, reducing irritation, inflammation and thelike.

[0184] Treatment of dermatoses or any other indications known ordiscovered to be susceptible to treatment by retinoic acid-likecompounds will be effected by administration of the therapeuticallyeffective dose of one or more compounds of the instant invention. Atherapeutic concentration will be that concentration which effectsreduction of the particular condition, or retards it expansion. Incertain instances, the compound potentially may be used in prophylacticmanner to prevent onset of a particular condition.

[0185] A useful therapeutic or prophylactic concentration will vary fromcondition to condition and in certain instances may vary with theseverity of the condition being treated and the patient's susceptibilityto treatment. Accordingly, no single concentration will be uniformlyuseful, but will require modification depending on the particularitiesof the disease being treated. Such concentrations can be arrived atthrough routine experimentation. However, it is anticipated that in thetreatment of, for example, acne, or similar dermatoses, that aformulation containing between 0.01 and 1.0 milligrams per milliliter offormulation will constitute a therapeutically effective concentrationfor total application. If administered systemically, an amount between0.01 and 5 mg per kg per day of body weight would be expected to effecta therapeutic result in the treatment of many diseases for which thesecompounds are useful.

[0186] Those partial or pan retinoid antagonist compounds of theinvention, when used to take advantage of their antagonist property, canbe co-administered to mammals, including humans, with retinoid agonistsand, by means of pharmacological selectivity or site-specific delivery,preferentially prevent the undesired effects of certain retinoidagonists. The antagonist compounds of the invention can also be used totreat Vitamin A overdose, acute or chronic, resulting either from the isexcessive intake of vitamin A supplements or from the ingestion of liverof certain fish and animals that contain high levels of Vitamin A. Stillfurther, the antagonist compounds of the invention can also be used totreat acute or chronic toxicity caused by retinoid drugs. It has beenknown in the art that the toxicities observed with hypervitaminosis Asyndrome (headache, skin peeling, bone toxicity, dyslipidemias) aresimilar or identical with toxicities observed with other retinoids,suggesting a common biological cause, that is RAR activation. Becausethe antagonist compounds of the present invention block RAR activation,they are suitable for treating the foregoing toxicities.

[0187] Generally speaking, for therapeutic applications in mammals, theantagonist compounds of the invention can be administered enterally ortopically as an antidote to vitamin A, or antidote to retinoid toxicityresulting from overdose or prolonged exposure, after intake of thecausative factor (vitamin A, vitamin A precursor, or other retinoid) hasbeen discontinued. Alternatively, the antagonist compounds of theinvention are co-administered with retinoid drugs, in situations wherethe retinoid provides a therapeutic benefit, and where theco-administered antagonist compound alleviates or eliminates one or moreundesired side effects of the retinoid. For this type of application theantagonist compound may be administered in a site-specific manner, forexample as a topically applied cream or lotion while the co-administeredretinoid may be given enterally. For therapeutic applications theantagonist compounds of the invention, like the retinoid agonistscompounds, are incorporated into pharmaceutical compositions, such astablets, pills, capsules, solutions, suspensions, creams, ointments,gels, salves, lotions and the like, using such pharmaceuticallyacceptable excipients and vehicles which per se are well known in theart. For topical application, the antagonist compounds of the inventioncould also be administered as a powder or spray, particularly in aerosolform. If the drug is to be administered systemically, it may beconfected as a powder, pill, tablet or the like or as a syrup or elixirsuitable for oral administration. For intravenous or intraperitonealadministration, the compound will be prepared as a solution orsuspension capable of being administered by injection. In certain cases,it may be useful to formulate these compounds by injection. In certaincases, it may be useful to formulate these compounds in suppository formor as extended release formulation for deposit under the skin orintramuscular injection.

[0188] The antagonist compounds also, like the retinoid agonists of theinvention, will be administered in a therapeutically effective dose. Atherapeutic concentration will be that concentration which effectsreduction of the particular condition, or retards its expansion. Whenco-administering the compounds of the invention to blockretinoid-induced toxicity or side effects, the antagonist compounds ofthe invention are used in a prophylactic manner to prevent onset of aparticular condition, such as skin irritation.

[0189] A useful therapeutic or prophylactic concentration will vary fromcondition to condition and in certain instances may vary with theseverity of the condition being treated and the patient's susceptibilityto treatment. Accordingly, no single concentration will be uniformlyuseful, but will require modification depending on the particularitiesof the chronic or acute retinoid toxicity or related condition beingtreated. Such concentrations can be arrived at through routineexperimentation. However, it is anticipated that a formulationcontaining between 0.01 and 1.0 milligrams per mililiter of formulationwill constitute a therapeutically effective concentration for totalapplication. If administered systemically, an amount between 0.01 and 5mg per kg per day of body weight would be expected to effect atherapeutic result.

[0190] General Embodiments and Synthetic Methodology

[0191] Definitions

[0192] The term alkyl refers to and covers any and all groups which areknown as normal alkyl, branched-chain alkyl and cycloalkyl. The termalkenyl refers to and covers normal alkenyl, branch chain alkenyl andcycloalkenyl groups having one or more sites of unsaturation. Similarly,the term alkynyl refers to and covers normal alkynyl, and branch chainalkynyl groups having one or more triple bonds.

[0193] Lower alkyl means the above-defined broad definition of alkylgroups having 1 to 6 carbons in case of normal lower alkyl, and asapplicable 3 to 6 carbons for lower branch chained and cycloalkylgroups. Lower alkenyl is defined similarly having 2 to 6 carbons fornormal lower alkenyl groups, and 3 to 6 carbons for branch chained andcyclo-lower alkenyl groups. Lower alkynyl is also defined similarly,having 2 to 6 carbons for normal lower alkynyl groups, and 4 to 6carbons for branch chained lower alkynyl groups.

[0194] The term “ester” as used here refers to and covers any compoundfalling within the definition of that term as classically used inorganic chemistry. It includes organic and inorganic esters. Where B (ofFormula 1 through 6) is —COOH, this term covers the products derivedfrom treatment of this function with alcohols or thiols preferably withaliphatic alcohols having 1-6 carbons. Where the ester is derived fromcompounds where B is —CH₂OH, this term covers compounds derived fromorganic acids capable of forming esters including phosphorous based andsulfur based acids, or compounds of the formula —CH₂OCOR₁₁ where R₁₁ isany substituted or unsubstituted aliphatic, aromatic, heteroaromatic oraliphatic aromatic group, preferably with 1-6 carbons in the aliphaticportions.

[0195] Unless stated otherwise in this application, preferred esters arederived from the saturated aliphatic alcohols or acids of ten or fewercarbon atoms or the cyclic or saturated aliphatic cyclic alcohols andacids of 5 to 10 carbon atoms. Particularly preferred aliphatic estersare those derived from lower alkyl acids and alcohols. Also preferredare the phenyl or lower alkyl phenyl esters.

[0196] Amides has the meaning classically accorded that term in organicchemistry. In this instance it includes the unsubstituted amides and allaliphatic and aromatic mono- and di-substituted amides. Unless statedotherwise in this application, preferred amides are the mono- anddi-substituted amides derived from the saturated aliphatic radicals often or fewer carbon atoms or the cyclic or saturated aliphatic-cyclicradicals of 5 to 10 carbon atoms. Particularly preferred amides arethose derived from substituted and unsubstituted lower alkyl amines.Also preferred are mono- and disubstituted amides derived from thesubstituted and unsubstituted phenyl or lower alkylphenyl amines.Unsubstituted amides are also preferred.

[0197] Acetals and ketals include the radicals of the formula-CK where Kis (—OR)₂. Here, R is lower alkyl. Also, K may be —OR₇O— where R₇ islower alkyl of 2-5carbon atoms, straight chain or branched.

[0198] A pharmaceutically acceptable salt may be prepared for anycompounds in this invention having a functionality capable of forming asalt, for example an acid functionality. A pharmaceutically acceptablesalt is any salt which retains the activity of the parent compound anddoes not impart any deleterious or untoward effect on the subject towhich it is administered and in the context in which it is administered.

[0199] Pharmaceutically acceptable salts may be derived from organic orinorganic bases. The salt may be a mono or polyvalent ion. Of particularinterest are the inorganic ions, sodium, potassium, calcium, andmagnesium. Organic salts may be made with amines, particularly ammoniumsalts such as mono-, di- and trialkyl amines or ethanol amines. Saltsmay also be formed with caffeine, tromethamine and similar molecules.Where there is a nitrogen sufficiently basic as to be capable of formingacid addition salts, such may be formed with any inorganic or organicacids or alkylating agent such as methyl iodide. Preferred salts arethose formed with inorganic acids such as hydrochloric acid, sulfuricacid or phosphoric acid. Any of a number of simple organic acids such asmono-, di- or tri- acid may also be used.

[0200] Some of the compounds of the present invention may have trans andcis (E and Z) isomers. In addition, the compounds of the presentinvention may contain one or more chiral centers and therefore may existin enantiomeric and diastereomeric forms. Still further oxime andrelated compounds of the present invention may exist in syn and antiisomeric forms. The scope of the present invention is intended to coverall such isomers per se, as well as mixtures of cis and trans isomers,mixtures of syn and anti isomers, mixtures of diastereomers and racemicmixtures of enantiomers (optical isomers) as well. In the presentapplication when no specific mention is made of the configuration (cis,trans, syn or anti or R or S) of a compound (or of an asymmetric carbon)then a mixture of such isomers, or either one of the isomers isintended. In a similar vein, when in the chemical structural formulas ofthis application a straight line representing a valence bond is drawn toan asymmetric carbon, then isomers of both R and S configuration, aswell as their mixtures are intended. Defined stereochemistry about anasymmetric carbon is indicated in the formulas (where applicable) by asolid triangle showing β configuration, or by a hashed line showing αconfiguration.

[0201] Referring now to the nomenclature used in naming the compounds ofthe invention and intermediate compounds leading thereto, the system fornumbering the tetrahydronaphthalene ring is demonstrated as shown by thestructural formulas of Compounds F, G and A2. Compound A2 is anexemplary compound of the invention within the scope of Formula 2 andCompounds F and G are two exemplary intermediates utilized in thesynthesis of the compounds of the invention. The numbering systemsillustrated here corresponds substantially to IUPAC rules, and will bereadily apparent to those skilled in the art as it is applied in theensuing description.

[0202] Generally speaking, the compounds of the invention are made insynthetic steps which involve the formation of thetetrahydronaphthalene, dihydronaphthalene, indane or suberane moiety,substituted with the desired R₁, R₂ and R₃ groups and with a reactivegroup, such as bromo group, that allows coupling with a reagent thatintroduces the -Z-Y(R₂)-A-B group. Such a reagent can be generallydescribed as X₃-Z-Y(R₂)-A-B

[0203] where X₃ is a reactive group, in many instances a leaving group,such as halogen. The -Z-Y(R₂)-A-B group may also be formed in a seriesof reactions performed starting with the tetrahydronaphthalene,dihydronaphthalene, indane or suberane molecule that has the appropriatereactive group or reactive position. in the aromatic nucleus.

[0204] The substituent or substituents in the 5 or 8 positions of thetetrahydronaphthalene or dihydronaphthalene (and by analogy in the iscorresponding positions of indane and suberan) which are designated asR₄ and X₂R₅ in Formula 1, as (X₂R₁₈)₂ in Formula 2, =C(R₁₉)₂ in Formula3, N=Z₂ in Formula 4, X₂R₂₀ in Formula 5 and R₁₄ in Formula 6 may beintroduced into the tetrahydronaphthalene or dihydronaphthalene ringmoiety before coupling with the reagent X₃-Z-Y(R₂)-A-B, or beforeformation of the -Z-Y(R₁)-A-B group. In other examples coupling with thereagent X₃-Z-Y(R₂)-A-B or formation of the -Z-Y(R₂)-A-B group attachedto the tetrahydronaphthalene or dihydronaphthalene nucleus is performedfirst to yield an intermediate that includes the tetrahydronaphthalene,dihydronaphthalene (and by analogy indane or suberane) moiety covalentlylinked to the -Z-Y(R₂)-A-B group, but which has a reactive group,preferably such as an oxo or trifluoromethanesulfonyloxy function, inthe 5 or 8 position. In these cases the substituents of these twopositions, as defined in Formulas 1-6, are introduced into theintermediate by appropriate reactions which are described in detailbelow.

[0205] The synthetic methodology employed for the synthesis of thecompounds of the present invention may also include transformations ofthe group designated as -A-B in Formulas 1-6. Generally speaking thesetransformations involve reactions well within the skill of thepracticing organic chemist. In this regard the following well known andpublished general principles and synthetic methodology are brieflydescribed.

[0206] Carboxylic acids are typically esterified by reflexing the acidin a solution of the appropriate alcohol in the presence of an acidcatalyst such as hydrogen chloride or thionyl chloride. Alternatively,the carboxylic acid can be condensed with the appropriate alcohol in'thepresence of dicyclohexylcarbodiimide and dimethylaminopyridine. Theester is recovered and purified by conventional means. Acetals andketals are readily made by the method described in March, “AdvancedOrganic Chemistry,” 2nd Edition, McGraw-Hill Book Company, p 810).Alcohols, aldehydes and ketones all may be protected by formingrespectively, ethers and esters, acetals or ketals by known methods suchas those described in McOmie, Plenum Publishing Press, 1973 andProtecting Groups, Ed. Greene, John Wiley & Sons, 1981.

[0207] To increase the value of n in the compounds of X₃-Z-Y(R₂)-A-B orprecursors thereof, before affecting the coupling or linkage with thetetrahydronaphthalene, dihydronaphthalene nucleus (where such compoundsare not available from a commercial source) aromatic or heteroaromaticcarboxylic acids are subjected to homologation by successive treatmentunder Arndt-Eistert conditions or other homologation procedures.Alternatively, derivatives which are not carboxylic acids may also behomologated by appropriate procedures. The homologated acids can then beesterified by the general procedure outlined in the preceding paragraph.

[0208] Compounds of formula X₃-Z-Y(R₂)-A-B (or of the invention as setforth in Formulas 1 through 6, as applicable) where A is an alkenylgroup having one or more double bonds can be made for example, bysynthetic schemes well known to the practicing organic chemist; forexample by Wittig and like reactions, or by introduction of a doublebond by elimination of halogen from an alpha-halo-arylalkyl-carboxylicacid, ester or like carboxaldehyde. Compounds of formula X₃-Z-Y(R₂)-A-B(or of the invention as set forth in Formulas 1 through 6, asapplicable) where the A group has a triple (acetylenic) bond can be madeby reaction of a corresponding aromatic methyl ketone with strong base,such as lithium diisopropyl amide, reaction with diethyl chlorophosphateand subsequent addition of lithium diisopropylamide.

[0209] The acids and salts derived from compounds of the invention arereadily obtainable from the corresponding esters. Basic saponificationwith an alkali metal base will provide the acid. For example, an esterof the invention may be dissolved in a polarsolvent such as an alkanol,preferably under an inert atmosphere at room temperature, with about athree molar excess of base, for example, lithium hydroxide or potassiumhydroxide. The solution is stirred for an extended period of time,between 15 and 20 hours, cooled, acidified and the hydrolysate recoveredby conventional means.

[0210] The amide may be formed by any appropriate amidation means knownin the art from the corresponding esters or carboxylic acids. One way toprepare such compounds is to convert an acid to an acid chloride andthen treat that compound with ammonium hydroxide or an appropriateamine. For example, the ester is treated with an alcoholic base solutionsuch as ethanolic KOH (in approximately a 10% molar excess) at roomtemperature for about 30 minutes. The solvent is removed and the residuetaken up in an organic solvent such as diethyl ether, treated with adialkyl formamide and then a 10-fold excess of oxalyl chloride. This isall effected at a moderately reduced temperature between about −10degrees and +10 degrees C. The last mentioned solution is then stirredat the reduced temperature for 1-4 hours, preferably 2 hours. Solventremoval provides a residue which is taken up in an inert organic solventsuch as benzene, cooled to about 0 degrees C. and treated withconcentrated ammonium hydroxide. The resulting mixture is stirred at areduced temperature for 1-4 hours. The product is recovered byconventional means.

[0211] Alcohols are made by converting the corresponding acids to theacid chloride with thionyl chloride or other means (J. March, “AdvancedOrganic Chemistry”, 2nd Edition, McGraw-Hill Book Company), thenreducing the acid chloride with sodium borohydride (March, Ibid, pg.1124), which gives the corresponding alcohols. Alternatively, esters maybe reduced with lithium aluminum hydride at reduced temperatures.Alkylating these alcohols with appropriate alkyl halides underWilliamson reaction conditions (March, Ibid, pg. 357) gives thecorresponding ethers. These alcohols can be converted to esters byreacting them with appropriate acids in the presence of acid catalystsor dicyclohexylcarbodiimide and dimethylaminopyridine.

[0212] Aldehydes can be prepared from the corresponding primary alcoholsusing mild oxidizing agents such as pyridinium dichromate in methylenechloride (Corey, E. J., Schmidt, G., Tet. Lett., 399, 1979), or dimethylsulfoxide/oxalyl chloride in methylene chloride (Omura, K., Swern, D.,Tetrahedron. 1978. 34. 1651).

[0213] Ketones can be prepared from an appropriate aldehyde by treatingthe aldehyde with an alkyl Grignard reagent or similar reagent followedby oxidation.

[0214] Acetals or ketals can be prepared from the corresponding aldehydeor ketone by the method described in March, Ibid, p 810.

[0215] Reagents of formula X₃-Z-Y(R₂)-A-B (or compounds of the inventionas set forth in Formulas 1 through 6, as applicable) where B is H can beprepared from the corresponding halogenated aromatic or heteroaromaticcompounds, preferably where the halogen is I.

Specific Embodiments

[0216] With reference to the symbol Y in Formulas 1 through 6, thepreferred compounds of the invention are those where Y is phenyl,naphthyl, pyridyl, thienyl or furyl. Even more preferred are compoundswhere Y is phenyl, naphthyl or pyridyl. As far as substititutions on theY (phenyl), Y (pyridyl) and (Y) naphthyl groups are concerned, compoundsare preferred where the phenyl group is 1,4 (para) substituted, thenaphthyl group is 2,6 substituted and where the pyridine ring is 2,5substituted. (Substitution in the 2,5 positions in the “pyridine”nomenclature corresponds to substitution in the 6-position in the“nicotinic acid” nomenclature.) In the preferred compounds of theinvention there is no optional R₂ substituent on the Y group.

[0217] The A-B group of the preferred compounds is (CH₂)_(n)—COOH or(CH₂)_(n)—COOR₈, where R₈ is defined as above. Even more preferably n iszero and R₈ is lower alkyl.

[0218] Referring still to the preferred compounds of Formulas 1 through6, the X₁ group is preferably C(R₁)₂, that is the preferred compoundsare tetrahydronaphthalene or dihydronaphthalene derivatives. Thearomatic portion of the tetrahydronaphthalene or dihydronaphthalenemoiety is preferably substituted only by the -Z-Y(R₂)-A-B group. Inother words, in the preferred compounds there is no It substituent(other than hydrogen). Similarly, in the preferred compounds of theinvention there is no R substituent (other than hydrogen). The R₁substituent of the compounds of the invention is preferably lower alkyl,and even more preferably methyl.

[0219] Preferred Z groups are:

[0220] —(CR₁═CR₁)_(n′)— where n′ is 0, 1, or 3 (when n′ is 3 then Yrepresents a direct valence bond between the —(CR₁═CR₁)_(n′)— group andthe -A-B group),

[0221] —N═N—,

[0222] —CO—CR₁═CR₁—,

[0223] —COO—, and

[0224] —CONH—.

[0225] Referring now specifically to compounds in accordance withFormula 1, compounds in these series are preferred where X₂ is O, the R₄group is H, lower alkyl, or CH₂COOR₈, and R₅ is H, Si(C₁₋₆alkyl)₃,COR₁₄, C(R₁₅)(R₁₆)X₂R₁₇. COCH₃ for COR₁₄, and CH₂OCH₃ and2-(1-tetrahydropyranyl) for the C(R₁₅)(R₁₆)X₂R₁₇ group are particularlypreferred.

[0226] The most preferred compounds in accordance with Formula 1 arelisted below in the Table for Formula 1A and with reference to thatformula. Formula 1A

TABLE For Formula 1A Configuration, When Applicable Compound and orposition No. R₄ R₅ Z Y R₈ of substituent Z A-32 CH₂COOEt H CH═CH1,4-C₆H₄—¹ Et 2 B-3 H t-butyl — 2,6-C₁₀H₆ ² Et 2 dimethyl silyl B-4 H H— 2,6-C₁₀H₆ ² Et 2 B-5 H H — 2,6-C₁₀—H₆ ² H 2 B-8 H CH₂OCH₃ — 2,6-C₁₀H₆² Et 2 B-9 H CH₂OCH₃ — 2,6-C₁₀H₆ ² H 2 B-10 H COCH₃ — 2,6-C₁₀H₆ Et 2C-13 H H polyene⁴ — Et 2 C-19 H H polyene⁴ — H 2 C-26 H CH₂OCH₃ polyene⁴— Et 2 C-27 H CH₂OCH₃ polyene⁴ — H 2 C-29 H THP³ polyene⁴ — H 2 C-31 HTHP³ polyene⁴ — H 2 D-1 CH₂COOEt H —N═N— 1,4-C₆H₄ ¹ Et 2 D-5 H H —N═N—1,4-C₆H₄ ¹ Et 2 D-6 H CH₂OCH₃ —N═N— 1,4-C₆H₄ ¹ Et 2 D-7 H CH₂OCH₃ —N═N1,4-C₆H₄ ¹ H 2 D-27 H CH₂OCH₃ CO—CH═CH— 1,4-C₆H₄ ¹ H 3 E-32 H H CO—NH1,4-C₆H₄ ¹ Et 2 E-33 H H —CO—NH— 1,4-C₆H₄ ¹ H 2 E-34 H CH₂OCH₃ —CO—NH—1,4-C₆H₄ ¹ Et 2 E-35 H CH₂OCH₃ —CO—NH 1,4-C₆H₄ ¹ H 2 E-37 H H —CO—O—1,4-C₆H₄ ¹ (CH₂)₂Si(CH₃)₃ 2 E-38 H CH₂OCH₃ —CO—O— 1,4-C₆H₄ ¹(CH₂)₂Si(CH₃)₃ 2 E-39 H CH₂OCH₃ —CO—O— 1,4-C₆H₄ ¹ H 2 E-40 H H —CO—O—1,4-C₆H₄ ¹ H 2 E-41 H CH₂OCH₃ —CO—O— 1,4-C₆H₄ ¹ Et 2 E-49 CH₂COOEt COCH₃—CO—NH— 1,4-C₆H₄ ¹ Et 2 E-54 CH₂COOEt H —CO—O— 1,4-C₆H₄ ¹ Et 2 E-56 HTHP³ —CO—O— 1,4-C₆H₄ ¹ Et 2 E-60 H THP³ —CO—O— 1,4-C₆H₄ ¹ Benzyl 2 E-64H THP³ —CO—O— 1,4-C₆H₄ ¹ H 2 E-65 H THP³ —CO—O— 1,4-C₆H₄ ¹ H 2 E-66 HTHP³ —CO—O— 1,4-C₆H₄ ¹ H 2 E-67 H THP³ —CO—O— 1,4-C₆H₄ ¹ H 2 E-70 H THP³—CO—NH 1,4-C₆H₄ ¹ Et 2 E-72 H THP³ —CO—NH— 1,4-C₆H₄ ¹ Et 2 E-74 H THP³—CO—NH 1,4-C₆H₄ ¹ H 2 E-75 H THP³ —CO—NH 1,4-C₆H₄ ¹ H 2 E-76 H THP³—CO—NH 1,4-C₆H₄ ¹ H 2 E-77 H THP³ —CO—NH 1,4-C₆H₄ ¹ H 2 E-82 H H —CO—O—1,4-C₆H₄ ¹ Benzyl 2

[0227] Referring now to compounds in accordance with Formula 2,compounds in these series are preferred where the two X₂R₁₈ jointlysymbolize an oxo (═O) group, or where the two X₂R₁₈ groups eachsymbolize an S-alkyl group, or where where the two X₂R₁₈ groups jointlysymbolize two sulphur atoms connected with a alkyledene bridge as in acyclic thioketal function.

[0228] The most preferred compounds in accordance with Formula 2 arelisted below in the Table for Formula 2A and with reference to thatformula. Formula 2A

TABLE FOR FORMULA ZA Compound No. X₂ R₁₈ Z Y R₈ A-2 O¹ — —CH═CH—1,4-C₆H₄ ² Et A-2a O¹ — —CH═CH— 1,4-C₆H₄ ² H A-23 S (CH₂)₃ ³— —CH═CH—1,4-C₆H₄ ² Et A-24 S (CH₂)₃ ³— —CH═CH— 1,4-C₆H₄ ² H B-1 — H⁴ — 2,6-C₁₀H₆⁵ Et B-2 — H⁴ — 2,6-C₁₀H₆ ⁵ H B-6 O¹ — — 2,6-C₁₀H₆ ⁵ Et B-7 O¹ — —2,6-C₁₀H₆ ⁵ H C-5 O¹ — polyene⁶ — Et D-10 O¹ — —N═N— 1,4-C₆H₄ ² Et E-28O¹ — —CO—NH— 1,4-C₆H₄ ² Et E-29 O¹ — —CO—NH— 1,4-C₆H₄ ² H E-36 O¹ ——COO— 1,4-C₆H₄ ² (CH₂)₂Si(CH₃)₃ E-44 O¹ — —COO— 1,4-C₆H₄ ² Et E-81 O¹ ——COO— 1,4-C₆H₄ ² benzyl

[0229] Compounds in accordance with Formula 3 are preferred where theR₁, groups are alkyl, especially lower alkyl most preferably methyl orethyl, where the two R₁, groups together with the methyledene carbonform a 5 or 6 membered ring, and where the R₁₉ groups are phenyl.Compounds are also preferred in accordance with this formula where oneof the R₁₉ groups is COOR₈, or COOH, and the other is H.

[0230] The most preferred compounds in accordance with Formula 3 arelisted below in the Table for Formula 3A and with reference to thatformula. Formula 3A

TABLE FOR FORMULA 3A Configuration when applicable Compound and/orposition No. R₁₉′ R₁₉″ Z Y R₈ of substituent A-25 CH₃ CH₃ —CH═CH—1,4-C₆H₄ ¹ Et 2 A-26 CH₃ CH₃ —CH═CH— 1,4-C₆H₄ ¹ H 2 A-27 CH₂CH₃ CH₂CH₃—CH═CH— 1,4-C₆H₄ ¹ Et 2 A-28 CH₂CH₃ CH₂CH₃ —CH═CH— 1,4-C₆H₄ ¹ H 2 A-29(CH₂)₅ ² — —CH═CH— 1,4-C₆H₄ ¹ Et 2 A-31 (CH₂)₅ ² — —CH═CH— 1,4-C₆H₄ ¹ H2 C-17a COOEt H polyene³ — Et 2, anti C-17b COOEt H polyene³ — Et 2, synC-36 CH₃ CH₃ polyene³ — Et 2 C-41 phenyl phenyl polyene³ — Et 2 D-2aCOOEt H —N═N— 1,4-C₆H₄ ¹ Et 2 D-23 CH₃ CH₃ —CO—CH═CH— 1,4-C₆H₄ ¹ H 3E-13 CH₃ CH₃ —COO— 1,4-C₆H₄ ¹ CH₂CH₂SiMe₃ 2 E-14 CH₃ CH₃ —COO— 1,4-C₆H₄¹ H 2 E-15 CH₃ CH₃ —COO— 1,4-C₆H₄ ¹ Et 2 E-16 CH₃ CH₃ —CONH— 1,4-C₆H₄ ¹Et 2 E-17 CH₃ CH₃ —CONH— 1,4-C₆H₄ ¹ H 2 E-50a COOEt H —CONH— 1,4-C₆H₄ ¹Et 2 E-52 COOH H —CONH— 1,4-C₆H₄ ¹ H 2, cis E-53 COOH H —CONH— 1,4-C₆H₄¹ H 2, trans

[0231] Referring now to compounds in accordance with Formula 4,compounds in these series are preferred where the Z₂ group is O-loweralkyl, especially OCH₃ or OCH₂OCH₃. The most preferred compounds inaccordance with Formula 4 are listed below in the Table for Formula 4Aand with reference to that formula. Formula 4A

TABLE FOR FORMUlA 4A Position of Z Substituent and/or Compoundconfiguration as No. Z₂ Z Y R₈ Applicable A-3 OCH₃ —CH═CH— 1,4-C₆H₄ ¹ Et2, anti A-4 OCH₃ —CH═CH— 1,4-C₆H₄ ¹ H 2, anti A-5 OCH₂CH₃ —CH═CH—1,4-C₆H₄ ¹ Et 2, anti A-6 OCH₃CH₃ —CH═CH— 1,4-C₆H₄ ¹ H 2, anti A-7 OH—CH═CH— 1,4-C₆H₄ ¹ Et 2, anti A-8 OH —CH═CH— 1,4-C₆H₄ ¹ H 2, anti B-11OCH₃ — 2,6-C₁₀H₆ ² Et 2, anti B-12 OCH₃ — 2,6-C₁₀H₆ ² H 2, anti C-6 OCH₃polyene³ — Et 2, anti C-22a OCH₃CH₃ polyene³ — Et 2, syn C-22b OCH₂CH₃polyene³ — Et 2, anti C-24 OCH₂CH₃ polyene³ — H 2, syn C-25 OCH₂CH₃polyene³ — H 2, anti D-3 OCH₃ —N═N— 1,4-C₆H₄ ¹ Et 2, anti D-4 OCH₃ —N═N—1,4-C₆H₄ ¹ H 2, anti D-29 OCH₃ —CO—CH═CH— 1,4-C₆H₄ ¹ H 3 E-30 OCH₃—CONH— 1,4-C₆H₄ ¹ Et 2, anti E-31 OCH₃ —CONH— 1,4-C₆H₄ ¹ H 2, anti E-42OCH₃ —COO— 1,4-C₆H₄ ¹ (CH₃)SiMe₃ 2, anti E-43 OCH₃ —COO— 1,4-C₆H₄ ¹ H 2,anti E-46 OCH₃ —COO— 1,4-C₆H₄ ¹ Et 2, anti

[0232] Compounds in accordance with Formula 5 are preferred where theR₂₀ group is lower alkyl, phenyl or SO₂CF₃.

[0233] The most preferred compounds in accordance with Formula 5 arelisted below in the Table for Formula 5A and with reference to thatformula. Formula 5A

TABLE FOR FORMULA 5A Compound No. X₂ R₂₀ Z Y R₈ A-9 O SO₂CF₃ —CH═CH—1,4-C₆H₄ ¹ Et A-16 S phenyl —CH═CH— 1,4-C₆H₄ ¹ Et A-18 S phenyl —CH═CH—1,4-C₆H₄ ¹ H A-17 SO₂ phenyl —CH═CH— 1,4-C₆H₄ ¹ Et A-19 SO₂ phenyl—CH═CH— 1,4-C₆H₄ ¹ H A-20 S CH₂CH₃ —CH═CH— 1,4-C₆H₄ ¹ Et A-21 S CH₂CH₃—CH═CH— 1,4-C₆H₄ ¹ H A-22 SO₂ CH₂CH₃ —CH═CH— 1,4-C₆H₄ ¹ H C-10 S phenylpolyene² — Et C-11 SO₂ phenyl polyene² — Et C-12 SO phenyl polyene² — EtC-14 O SO₂CF₃ polyene² — Et C-28 O trimethylsilyl polyene² — Et D-11 OSO₂CF₃ —N═N— 1,4-C₆H₄ ¹ Et E-20 S phenyl —CONH— 1,4-C₆H₄ ¹ Et E-21 Sphenyl —CONH— 1,4-C₆H₄ ¹ H E-22 SO₂ phenyl —CONH— 1,4-C₆H₄ ¹ H E-23 Sphenyl —COO— 1,4-C₆H₄ ¹ Et E-24 SO₂ phenyl —COO— 1,4-C₆H₄ ¹ Et E-25 Sphenyl —COO— 1,4-C₆H₄ ¹ (CH₂)₂Si(CH₃)₃ E-26 S phenyl —COO— 1,4-C₆H₄ ¹ HE-27 SO₂ phenyl —COO— 1,4-C₆H₄ ¹ H

[0234] Referring now to compounds in accordance with Formula 6,compounds in these series are preferred where the R₁₄ group isthiazolyl, more preferably 2-thiazolyl, thienyl, more preferably2-thienyl, branched chain lower alkyl, more preferably t-butyl, or whereR₁₄ is CH₂COOR₈ or CH₂COOH.

[0235] The most preferred compounds in accordance with Formula 6 arelisted below in the Table; for Formula 6A and with reference to thatformula. Formula 6A

TABLE FOR FORMULA 6A Position Compound of Z Sub No. R₁₄ Z Y R₈ stituentA-10 2-thiazolyl —CH═CH— 1,4-C₆H₄ ¹ Et 2 A-12 2-thiazolyl —CH═CH—1,4-C₆H₄ ¹ H 2 A-13 2-thienyl —CH═CH— 1,4-C₆H₄ ¹ Et 2 A-15 2-thienyl—CH═CH— 1,4-C₆H₄ ¹ H 2 C-15 2-thienyl polyene² — Et 2 C-20 2-thienylpolyene² — H 2 C-46 t-butyl polyene² — Et 2 D-2b CH₂COOEt —N═N— 1,4-C₆H₄¹ Et 2 D-12 2-thienyl —N═N— 1,4-C₆H₄ ¹ Et 2 D-13 2-thienyl —N═N—1,4-C₆H₄ ¹ H 2 D-18 CH₂COOEt CO—CH═CH— 1,4-C₆H₄ ¹ H 3 D-20 t-butyl—CO—CH═CH— 1,4-C₆H₄ ¹ H 3 D-34 2-thienyl CO—CH═CH— 1,4-C₆H₄ ¹ H 3 E-72-thienyl —CO—NH— 1,4-C₆H₄ ¹ Et 2 E-8 2-thienyl —CO—NH— 1,4-C₆H₄ ¹ H 2E-9 2-thienyl —COO— 1,4-C₆H₄ ¹ Et 2 E-10 2-thienyl —COO— 1,4-C₆H₄ ¹(CH₂)₂SiMe₃ 2 E-11 2-thienyl —COO— 1,4-C₆H₄ ¹ H 2 E-50b CH₂—COOEt—CO—NH— 1,4-C₆H₄ ¹ Et 2 E-55 CH₂COOEt —COO— 1,4-C₆H₄ ¹ Et 2 E-79 t-butyl—CO—NH— 1,4-C₆H₄ ¹ Et 2 E-80 t-butyl —CO—NH— 1,4-C₆H₄ ¹ H 2

[0236] The compounds of this invention can be made by the generalprocedures outlined above under the title “GENERAL EMBODIMENTS ANDSYNTHETIC METHODOLOGY”. The following chemical pathways represent thepresently contemplated best synthetic routes to certain exemplarycompounds of the invention illustrated here. However, the syntheticchemist will readily appreciate that the conditions set out here forthese specific embodiments can be generalized to any and all of thecompounds represented by Formulas 1 through 6.

[0237] Important starting materials for the synthesis of the preferredcompounds of the invention are6-bromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound F),7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1-one (Compound G), and theisomeric bromo compound,6-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound H).Compound G can be obtained as described in J. Med. Chem. 1995, 38,4764-4767, and as shown in Reaction Scheme 1. Thus, referring nowspecifically to Reaction Scheme 1, ethyl 3-bromophenylacetate (CompoundB, made by esterification of 3-bromophenylacetic acid) is reduced withdiisobutylaluminum hydride (DIBAL H) to yield(3-bromophenyl)acetaldehyde. (3-Bromophenyl)acetaldehyde is reacted in aWittig reaction with (carbethoxymethylene)triphenylphosphorane toprovide a mixture of E and Z ethyl 4-(3-bromophenyl)but-2-enoates. Thelatter con pounds are hydrogenated to yield ethyl4-(3-bromophenyl)butanoate (Compound D). Compound D is reacted with theGrignard reagent derived from methylbromide to give the is tertiaryalcohol 5-(3-bromophenyl)-2-methylpentan-2-ol (Compound E) (It should beapparent to those skilled in the art, that the choice of the Grignardreagent used in this reaction step determines the nature of the R₁substituent in the resulting compounds of the invention.) Compound E isthen treated with acid to cyclize it and to form6-bromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound F).Compound F is oxidized with chromium trioxide to yield7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound G). Theisomeric compound, 6-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one(Compound H) can be obtained, starting with ethyl(4-bromophenyl)acetate, in accordance with the sequence of reactionsillustrated in Reaction Scheme 1 for Compound G.6-Bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound H) canalso be obtained in accordance with the published literature procedure:Mathur et al. Tetrahedron, 41, 1509-1516 (1985).

[0238] Another important starting material for the synthesis of severalpreferred compounds of the invention is3,4-dihydro-4,4-dimethyl-7-aminonaphthalen-1(2H)-one (Compound D9) whichis prepared from the known 3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one,by nitration and subsequent catalytic reduction of the intermediate3,4-dihydro-4,4-dimethyl-7-nitronaphthalen-1(2H)-one (Compound D8), asis described in the enclosed description of specific examples,

[0239] Still other important starting materials for the synthesis ofseveral preferred compounds of the invention are the isomeric3,4-dihydro-4,4-dimethyl-7-acetyl-naphthalen-1(2H)-one (Compound D14a);and 3,4-dihydro-4,4-dimethyl-6-acetyl-naphthalen-1(2H)-one (CompoundD14b). These are prepared by reacting1,2,3,4-tetrahydro-1,1-dimethylnaphthalene with acetyl chloride in aFriedel-Crafts type reaction, followed by oxidation with chromiumtrioxide of the isomeric acetyl derivatives. These compounds can also beobtained by an alternative procedure from Compounds G and Hrespectively. The experimental conditions of these preparations aredisclosed in the description of the specific examples.

[0240] Yet another important starting material for the synthesis ofseveral preferred compounds of the invention is methyl5,5-dimethyl-5,6-dihydro-naphthalen-8(7H)-one-2-carboxylate (CompoundE2) which can be made by reaction of7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1-one (Compound G) with CO₂in the presence of t-butyl lithium, but is more advantageously preparedin the presence of palladium(II)-bis(triphenylphosphine)chloride and1,3-bis(diphenylphosphino)propane catalysts by reaction withcarbonmonoxide and methanol, as is described in the specific examples.

[0241] Referring now to Reaction Scheme 2 the synthesis of preferredexamples of compounds of the invention are described, where the Z group,with reference to Formulas 1-6 is —CH═CH—. Compounds of this type of theinvention are advantageously obtained in a direct coupling reactionbetween an ethenyl compound such as ethyl 4-vinylbenzoate, and a 6- or7-bromonaphthalene-1(2H)-one derivative, such as Compound G or CompoundH in a reaction commonly known as the Heck reaction. Reaction Scheme 2exemplifies this reaction with7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound G) as thestarting material. A general formula for the ethenyl compounds which aresuitable as reagents in the Heck reaction to provide these type ofcompounds of the invention is CH═CH₂—Y(R₂)-A-B where the symbols havethe same meaning as defined in connection with Formulas 1-6. Thesecompounds are readily available in accordance with the chemicalliterature, or otherwise in accordance with state-of-the-art. The Heckreaction is well known in the art, and is usually conducted in a basicsolvent, such as triethylamine, in the presence of a phosphine catalyst(such as tris(2-methylphenyl)phosphine or tri-O-tolylphosphine) in thepresence of palladium(II)acetate catalyst.

[0242] Those skilled in the art will readily understand that thecompounds of the invention which have an ethylene (—CH═CH—) orsubstituted ethylene (—CR₁═CR₁—) linking group can also be made by aWittig or like (Horner Emmons) reactions, which are per se well known inthe art. Those skilled in the art will also readily understand that thereaction sequence shown in Reaction Scheme 2 can be readily adapted forcompounds where the tetrahydronaphthalene (or other rings within thescopes of Formulas 1-6) have R₁, R₂ and R₃ substituents other thanspecifically shown in this reaction scheme.

[0243] Thus in the example shown in Reaction Scheme 27-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound G) isreacted with ethyl 4-vinylbenzoate to yield ethyl(E)[2-(5,6dihydro-5,5-dimethylnaphthalen-8(7H)-one-2-yl)ethenyl]-benzoate(Compound A2). Ethyl 4-vinylbenzoate is available in accordance with thechemical literature, Can. J. Chem (1973) 51, 897-914, which is expresslyincorporated herein by reference. Compound A2 is an example for thecompounds of the present invention within the scope of Formula 2.Compound A2 is reacted with methoxylamine hydrochloride in an alcoholicsolvent (such as ethanol) in the presence of sodium acetate to yield themethyl oxime, ethyl(E)-4-[2-(5,5-dimethyl-5,6,-dihydro-8(7H)-anti-(O-methyloxime)-naphthalen-2-yl)ethenyl]-benzoate (Compound A3). Compound A3 canbe saponified by treatment with base, such as LiOH, to provide the freecarboxylic acid,(E)-4-[2-(5,5-dimethyl-5,6,-dihydro-8(7H)-anti-(O-methyloxime)-naphthalen-2-yl)ethenyl]-benzoic acid (Compound A4). Compounds A3and A4 are compounds of the invention within the sope of Formula 4. Theconditions for the is saponification of Compound A3 to provide CompoundsA4 serve as example for several saponification reactions which yieldseveral compounds of the invention where the B group of Formulas 1-6 isa free carboxylic acid (COOH), or salt thereof.

[0244] Instead of methoxylamine hydrochloride, hydroxylaminehydrochloride, or ethoxylamine hydrochloride or other analogous reagentscan be used to obtain the oximes or other O-alkyl, O-aryl analogs ofCompounds A3 and A4, within the scope of Formula 4. Generally speakingand with reference to Formula 4, the oxo compounds, such as Compound A2are reacted with a reagent of the formula NH₂-Z₂, where Z. is defined asin connection with Formula 4. Thus, the oxo compounds analogous toCompound A2 are reacted with a reagent of the formula H₂N-Z₂ to yieldcompounds of Formula 4. As is known, when the reagent H₂N-Z₂ is NH₁OH orits salt, then the reaction is the formation of an oxime. Generallyspeaking the oximes are readily formed by reacting the oxo compoundswith hydroxylamin, hydrochloride in a polar solvent, such as a loweralkanol, in the presence of a buffering agent, such as sodium acetate.The reaction can be conducted under similar conditions with a reagent ofthe formula NH₂OR₁ or its salt (such as methoxylamine hydrochloride orethoxylamine hydrochloride as demonstrated in Reaction Scheme 2) toyield compounds of Formula 4 where Z₁ is OR₁ (R₁ is defined as inconnection with Formula 4). When the reagent H₂N-Z₂ is a primary aminethen the reaction is the formation of an imine. The latter reaction isusually conducted in a polar (alcoholic) solvent. Further reagents, inaccordance with the general formula H₂N-Z₂ are those where Z₂ isNHCON(R₁₄)₂ (formation of semicarbazone), NHCSN(R₁₄)₂ (formation ofthiosemicarbazone) and N(R₁₄)₂ (formation of a hydrazone). (The symbolR₁₄ is defined as in connection with Formula 4.) The semicarbazones,thiosemicarbazones and hydrazones corresponding to Formula 4 can beprepared under conditions which are well known in the art for theformation of such derivatives of ketone compounds. Usually theseconditions are similar to the conditions leading to the oximes describedabove. Typically, the hydrochloride salt of the reagent (semicarbazide,thiosemicarbazide or hydrazide) is reacted with the oxo compound such asCompound A2 in an alcoholic solvent, in the presence of sodium acetate.

[0245] Referring now again specifically to Reaction Scheme 2, ethyl(E)-4-[2-(5,6-dihydro-5,5-dimethylnaphthaten-8(7H)-one-2-yl)ethenyl]benzoate(Compound A2) is reacted with sodium bis(trimethylsilyl)amide and2-[N,N-bis(trifluoromethane-sulfonyl)amino]-5-chloropyridine in an inertether type solvent, such as tetrahydrofuran, at low temperatures (−78°C. and 0° C.). This provides first a sodium salt intermediate which isnot isolated and not shown in the reaction scheme. The reactionsultimately result in the trifluoromethylsulfonyloxy derivative ethyl(E)-4-[2-(5,6dihydro-5,5-dimethyl-8-(trifluoromethylsulfonyl)oxy-naphthalen-2-yl)ethenyl]-benzoate(Compound A9). Compound A9 is within the scope of Formula 5 of thepresent invention and is also an important intermediate for thesynthesis of several compounds of the invention within the scope ofFormula 6. Compound A9 is a trifluoromethylsulfonate derivative, whichsometimes also called a “triflate” in the trade, and the CF₃SO₂ group issometimes abbreviated as “Tf” in the reaction schemes.

[0246] As is shown further in Reaction Scheme 2 for the specificexamples of thiazole and thiophene, respectively yielding Compounds A10and A13, the triflate derivative Compound A9 is reacted with anorganometal derivative derived from the compound R₁₄H, such that theformula of the organometal derivative is R₁₄Met (Met stands formonovalent metal), preferably R₁₄Li. (R₁₄ is defined as in connectionwith Formula 6.) The reaction with the organometal derivative,preferably lithium derivative of the formula R₁₄Li is usually conductedin an inert ether type solvent (such as tetrahydrofuran) in the presenceof zinc chloride (ZnCl₂) and tetrakis(triphenylphosphine)palladium(0)(Pd(PPh₃)₄). The organolithium reagent R₁₄Li, if not commerciallyavailable, can be prepared from the compound R₁₄H (or its halogenderivative R₁₄—X₁ where X₁ is halogen) in an ether type solvent inaccordance with known practice in the art. The temperature range for thereaction between the reagent R₁₄Li and the triflate derivatives is,generally speaking in the range of approximately −78° C. to 50° C.Compounds A10 and A13 and their analogs can be saponified, or subjectedto further transformations, such as homologation and otherstate-of-the-art reactions which yield homologs and derivatives inaccordance with the reactions discussed above.

[0247] Reaction Scheme 2 serves as an example of synthetic methodologyused for preparing compounds of the present invention where the—Y(R₂)-A-B group of Formulas 1-6 is linked to the tetrahydronaphthalenenucleus with the desired Z group, before the final substitution patternis obtained by transformations of the a tetrahydronaphthalene (ordihydronaphthalene) moiety.

[0248] Reaction Scheme 3 provides further examples for the synthesis ofcompounds within the scope of Formula S where the linking group betweenthe dihydronaphthalene moiety and the Y group is —CH═CH—. In thesequence of reactions described here the oxo function of a startingtetrahydronaphthalene-one moiety is modified before a Heck couplingreaction is performed. Specifically, in the example shown in thereaction scheme, 7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one(Compound G) is reacted with thiophenol in the presence of titaniumtetrachloride and triethylamine in tetrahydrofuran (THF), to provide theintermediate 4,4-dimethyl-7-bromo-1-phenylthio-3,4-dihydronaphthalene(Compound A35). A similar reaction can be performed with ethanethiol asa reagent instead of thiophenol, to yield2-bromo-5,6-dihydro-5,5-dimethyl-8-ethylthio-naphthalene (Compound A36)and other analogous compounds which are not shown in the reactionscheme. Compound A35 is reacted in the Heck reaction to yield ethyl(E)-4-[2-(5,6-dihydro-5,5-dimethyl-8-phenylthio'naphthalenyl)ethenyl]benzoate (Compound A16). Compound A16 is saponified to yield thecarboxylic acid,(E)-4-[2-(5,6-dihydro-5,5-dimethyl-8-(phenylthio)-naphthalen-2-yl)ethenyl]benzoic acid (Compound A18), and is oxidized with m-chloroperoxybenzoicacid (MCPBA) to provide the corresponding phenylsulfonyl compound, ethyl(E)-4-[-2-(5,6-dihydro-5,5-dimethyl-8-(phenylsulfonyl)-naphthalenyl)ethenyl]benzoate(Compound A17). Compound A18 can also be oxidized under similarconditions to provide the free carboxylic acid (or salt thereof) of thephenylsulfonyl compound,(E)-4-[-2-(5,6-dihydro-5,5-dimethyl-8-phenylsulfonyl-naphthalenyl)ethenyl]benzoicacid (Compound A19).

[0249] Reaction Scheme 4 discloses further examples for the preparationof compounds of the invention within the scope of Formula 2 where thegroup linking the tetrahydronaphthalene and Y(R₂)-A-B moieties is—CH═CH—. As is shown in the scheme, ethyl(E)-4-[2-(5,6-dihydro-5,5-dimethylnaphthalen-8(7H)-one-2-yl)ethenyl]-benzoate(Compound A2) is reacted with 1,3-propanedithiol in the presence ofborontrifluoride diethyl etherate to yield the corresponding cyclicthioketal compound, ethyl(E)-4-[-2-(5,6,7,8-tetrahydro-5,5-dimethyl-8-(1,3-dithian-2-yl)naphthalen-2-yl)ethenyl]benzoate (Compound A23). Other ketal and thioketal analogs of thiscompound, within the scope of Formula 2 can be obtained by analogousreactions suitable for ketal and thioketal formation, which are per sewell known in the art. Saponification of Compound A23 provides thecorresponding free acid (or salt thereof),(E)4-[2-(5,6,7,8tetrahydro-5,5-dimethyl-8(2-(1,3-dithian-2-yl)naphthalenyl)ethenyl]-benzoicacid (Compound A24).

[0250] Reaction Scheme 5 provides examples for the synthesis ofcompounds of the invention within the scope of Formula 3. The synthesisof these compounds proceeds in accordance with methodology where thedesired substituent is introduced into the tetrahydronaphthalene moietybefore this moiety is coupled or linked to the desired Z-Y(R₂)A-B group,and in these examples also the Z group is —CH═CH—. Thus in accordancewith this scheme, 7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one(Compound G) is reacted in a McMurry coupling reaction with acetone toprovide7-bromo-1(2H)-(propyliden-2-yl)-3,4-dihydro-4,4-dimethylnaphthalene(Compound A37). The reaction (McMurry coupling) is conducted at elevatedtemperature in the presence of lithium metal and titanium trichloride,in an inert ether type solvent, for example in refluxing1,2-dimethoxyethane (DMB). In other examples which are described in theSpecific Examples, 3-pentanone, and cyclohexanone are used as ketonereagents, instead of the acetone shown in the reaction scheme. CompoundA37 is then subjected to a Heck coupling reaction with an ethenylreagent such as ethyl 4-vinylbenzoate shown in the scheme, to provideethyl(E)-4-[2-(5,6-dihydro-5,5-dimethyl-8(7H)-(propyliden-2-yl)-naphthalen-2-yl)ethenyl]benzoate(Compound A25). Compound A25 is saponified under conditions describedabove to provide(E)-4-[2-(5,6-dihydro-5,5-dimethyl-8(7H)-(propyliden-2-yl)-naphthalen-2-yl)ethenyl]-benzoicacid (Compound A26).

[0251] Reaction Scheme 5 discloses another example for the preparationof compounds within the scope of Formula 3. In this example thesubstituent is introduced to replace the oxo function oftetrahydronaphthalene-2-one after the Z-Y(R₂)-A-B group has already beencoupled to the tetrahydronaphthalene nucleus. Thus, ethyl(E)-4-[2-(5,6-dihydro-5,5-dimethyl-naphthalen-8(7H)-one-2-yl)ethenyl]-benzoate(Compound A2) is reacted with ethyl bromoacetate in the presence of zincmetal in a Reformatsky reaction to provide (+/−) ethyl(E)-4-[2-(5,6,7,8-tetrahydro-5,5-dimethyl-8-hydroxy-8-(carbethoxymethyl)naphthalen-2-yl)ethenyl]benzoate (Compound A32). Compound A32 is itself within the scope of thepresent invention, within the scope of Formula 1. Compound A32 isdehydrated, as shown in the example by treatment with (methoxycarbonylsulfamoyl)triethylammonium hydroxide (Burgess reagent) to yield amixture of ethyl(E)-4-[2-(5,6-dihydro-5,5-dimethyl-8-(carbethoxymethyl)naphthalen-2-yl)ethenyl]benzoate(Compound A33a), and ethyl (E)-4-[2-(5,6dihydro-5,5-dimethyl-8(7H)-anti(carbethoxymethylidenyl)-naphthalen-2-yl)ethenyl]benzoate (CompoundA33b). Compound A33a is within the scope of Formula 6, and Compound A33bis within the scope of Formula 3.

[0252] Reaction Scheme 6 provides examples for the synthesis ofcompounds of the invention where in accordance with Formulas 1-6 the Zgroup is —(CR₁═CR₁)_(n′)— and n′ is 0; in other words where there is nolinking group between the tetrahydronaphthalene or dihydronaphthalenenucleus and the Y(R₂)-A-B group. For the synthesis of these examples thestarting material is 6-bromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene(Compound F) which is reacted with n-butyl lithium andtriisopropylborate in an aprotic solvent such as toluene to give afterhydrolysis (5,6,7,8-tetrahydro-5,5-dimethylnaphth-2-yl)boronic acid(Compound B13). Compound B13 and related boronic acid derivatives (suchas Compound B14 in this scheme) are suitable for coupling with a reagenthaving the formula X₃—Y(R₂)-A-B where X₃ is halogen, and the remainingsymbols are defied as for Formulas 1-6. Reaction Scheme 6 illustratesthis coupling reaction with ethyl 6-bromo-naphthalene-2-carboxylate inthe presence of tetrakis-triphenyl-phosphine palladium(0) to yieldethyl-6-[5,6,7,8-tetrahydro-5,5-dimethyl-naphth-2-yl]naphthoate(Compound B1). Compound B1 of the invention is within the scope ofFormula 2. Other reagents corresponding to formula X₃—Y(R₂)-A-B arereadily available in accordance with the chemical literature and/or canbe obtained in accordance with state-of-the-art synthetic methodology.Examples for such other reagents are ethyl 4-bromobenzoate and ethyl2-bromopyridine-5-carboxylate.

[0253] Continuing on with the description of Reaction Scheme 6,6-bromo-1,2,3,4-tetrahydro-1,1-dimethyl-4-hydroxynaphthalene is reactedin the presence of base with t-butyldimethylsilyl chloride to provide6-bromo-1,2,3,4-tetrahydro-1,1-dimethyl-4-(t-butyldimethylsilyloxy)naphthalene(Compound B15). The starting6-bromo-1,2,3,4-tetrahydro-1,1-dimethyl-4-hydroxynaphthalene can beobtained by reduction of7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound G). Underconditions similar to the ones described above Compound B15 is convertedto the boronic acid derivative(5,5-dimethyl-8-(t-butyldimethylsilyloxy)-5,6,7,8-tetrahydro-naphth-2-yl)boronicacid (Compound B14). Compound B14 is then coupled with ethyl6-bromo-naphthalene-2-carboxylate to yield ethyl6-[5,6,7,8-tetrahydro-5,5-dimethyl-8-(t-butyldimethylsilyloxy)-naphth-2-yl]naphth-2-oate(Compound B3). Compound B3 is then reacted with tetrabutylammoniumfluoride to remove the t-butyldimethylsilyl blocking group and to giveethyl 6-[5,6,7,8-tetrahydro-5,5-dimethyl-8-hydroxynaphth-2-yl]naphth-2-oate (Compound B4). Compound B4 can be acylated togive ethyl6-[5,6,7,8-tetrahydro-5,5-dimethyl-8-(O-acetyl)-naphth-2-yl]naphth-2-oate(Compound B10), or methoxymethylated with methoxymethyl chloride in thepresence of base (preferably ethyl N,N-diisopropylamine, Hunig's base)to give ethyl6-[5,6,7,8-tetrahydro-5,5-dimethyl-8-(methoxymethyloxy)-naphth-2-yl]naphth-2-oate(Compound B8), and oxidized with N-methyl morpholine N-oxide to provideethyl-6-[5,5-dimethyl-5,6-dihydro—naphthlen-8(7-one-2-yl]-naphthalen-2-oate(Compound B6). Compounds B8 and B10 of the invention are within thescope of Formula 1, whereas Compound B6 is within the scope of Formula2. Compound B6 can be converted into the O-methyloxime (ethyl6-[5,5-dimethyl-5,6-dihydro—naphthlen-8(7H)-anti-(O-methyl-oxime)-2-yl]-naphthalen-2-oate(Compound B11) not shown in the scheme) and into other derivatives suchas oximes, imines, hydrazones and the like, as is described above inconnection with Reaction Scheme 2. Further derivatives of Compound B6(and of analogous compounds) wherein the 8-oxo function of the moleculeis modified can be obtained in accordance with the general syntheticmethodology described in this specification. For example thetrifluoromethylsulfonyl (triflate) derivative can be obtained in analogyto the reaction leading to Compound A9 as described in Reaction Scheme2, and the trifluoromethylsulfonyl (triflate) derivative is reacted withthe reagents R₁₄Me to provide compounds of Formula 6.

[0254] Reaction Scheme 7 discloses a preferred example of a syntheticroute leading to compounds of the invention where with reference toFormulas 1-6 the symbol Z represents —(CR₁═CR₁)_(n′)—, where n′ is 3,and there is no Y(R₂) group. Thus,4,4-dimethyl-7-acetyl-1,2,3,4-tetrahydronaphthalen-1(2H)-one (CompoundD14a) is reacted in a Horner Emmons type reaction withtriethylphosphonoacetate in the presence of sodium hydride in an ethertype solvent such as tetrahydrofuran. Conditions of the Horner Emmonsreaction are well known in the art, and it is also well known thatusually a related Wittig type reaction can also be employed using atrialkylphosphonium reagent instead of the phosphonate reagent, to yieldthe same products as is obtained in the Horner Emmons reaction. Theproduct of the Horner Emmons reaction in this example is ethyl3-[4,4-dimethyl-1,2,3,4,-tetrahydronaphthalen-1(2H)one-7-yl]but-2(E)-enoate(Compound C2) which is reduced with diisobutyl aluminum hydride toprovide3-[1-hydroxy-4,4-dimethyl-1,2,3,4,-tetrahydronaphthalen-7-yl]but-2(E)-en-1-ol(Compound C3). Compound C3 is oxidized back to the aldehyde and ketone“stage” with manganese dioxide to give3-[4,4-dimethyl-1,2,3,4,-tetrahydronaphthalen-1(2H)one-7-yl]but-2(E)-en-al(Compound C4). Compound C4 is subjected to yet another Horner Emmonstype reaction with diethyl-(E)-3-ethoxycarbonyl-2-methylalkylphosphonate(available from the chemical literature; see: Vuligunda et al. BiorganicMedical Chemistry Letters, (1996) 6 p213-218) in tetrahydrofuran in thepresence of n-butyl lithium, to yield ethyl7-[4,4-dimethyl-3,4,-dihydronaphthalen-1(2H)one-7-yl]-3,7-dimethyl-hept-2(E),4(E), 6(E)trienoate (Compound C5).

[0255] Compound C5 of the invention is within the scope of Formula 2,and is also readily converted to further compounds of the invention inaccordance with the generic principles disclosed in this specification.Several examples of reactions which provide further compounds of theinvention using Compound C5 as the starting material are shown inReaction Scheme 7. These reactions are described in less detail to theextent that they are of the types which have been described above. Thus,the “oxo” compound ethyl7-[4,4-dimethyl-3,4,-dihydronaphthalen-1(2Hone-7-yl]-3,7-dimethyl-hept-2(E),4(E), 6(E)trienoate (Compound C5) is saponified to yield the free acid(not shown in the scheme), is converted to the O-methyl-oxime derivative(Compound C16); to ethyl7-[4,4-dimethyl-3,4-dihydro-1-(trimethylsiloxy)-naphth-7-yl]3,7-dimethyl-hepta-2(E),4(E),6(E)-trienoate (1-trimethylsilyloxy derivative CompoundC28); and to ethyl7-[4,4-dimethyl-3,4,-dihydronaphthalen-1-trifluoromethylsulfonyloxy-7-yl]-3,7-dimethyl-hept-2(E),4(E), 6(E)trienoate (“triflate”, Compound C14). Compounds C14 and C28are within the scope of Formula 5, whereas Compound C16 is within thescope of Formula 4. Another Horner Emmons type reaction of Compound C5which leads to compounds within the scope of Formula 3 (Compounds 17aand 17B) is shown in the scheme.

[0256] In the examples shown in Reaction Scheme 7 the “oxo” compoundethyl7-[4,4-dimethyl-3,4,-dihydronaphthalen-1(2H)one-1-yl]-3,7-dimethyl-hept-2(E),4(E), 6(E)trienoate (Compound C5) is also reduced with ZnBH₄ to yieldthe corresponding secondary alcohol, ethyl7-[4,4-dimethyl-1,2,3,4,-tetrahydronaphthalen-1-hydroxy-7-yl]-3,7-dimethyl-hept-2(E),4(E), 6(E)trienoate (Compound C13). Compound C13 is reacted withchloromethylmethyl ether to give (−/+)ethyl7-[4,4-dimethyl-1,2,3,4-tetrahydro-1-(O-methoxymethyl)-naphth-7-yl]3,7-dimethyl-hepta-2(E),4(E),6(E)-trienoate (Compound C26); alternatively it is reacted with3,4-dihydro-2H-pyran in methylene chloride in the presence of p-toluenesulfonic acid (p-TsOH) to give the diastereomeric dihydropyranoxyderivatives, (+/−)ethyl7-[4,4-dimethyl-1,2,3,4-tetrahydro-1(RS)-(2′(RS)-tetrahydropyranoxy)-naphth-2-yl]-3,7-dimethyl-hepta-2(E),4(E),6(E)-trienoate(Compound C29a) and (+/−)ethyl7-[4,4-dimethyl-1,2,3,4-tetrahydro-1(RS)-(2′(SR)-tetrahydropyranoxy)-naphth-2-yl]-3,7-dimethyl-hepta-2(E),4(E),6(E)-trienoate(Compound C29b). Compounds C13, C26, C29a and C29b of the invention arewithin the scope of Formula 1.

[0257] The trifluoromethylsulfonate (triflate) derivative Compound C14is itself an important starting material for the syntheses of severalcompounds of the invention within the scope of Formula 6; among thesethe preparations of ethyl7-[4,4-dimethyl-3,4,-dihydronaphthalen-1-(2-thienyl)-7-yl]-3,7-dimethyl-hept-2(E),4(E), 6(E)trienoate (Compound C15) and of ethyl7-[4,4-dimethyl-3,4,-dihydronaphthalen-1-cyano-7-yl]-3,7-dimethyl-hept-2(E),4(E), 6(E)trienoate (Compound 21) are illustrated in the reactionscheme.

[0258] Reaction Scheme 8 discloses other examples for synthesizingpreferred compounds of the invention where with reference to Formula 5the symbol Z represents —(CR₁═CR₁)_(n′)—, where n′ is 3, and there is noY(R₂) group. The starting compound for the series of reactions shown inthis scheme is 4,4-dimethyl-7-bromo-1-phenylthio-3,4-dihydronaphthalene(Compound A35) which can be obtained as shown in Reaction Scheme 3.Thus, referring now to Reaction Scheme 8, Compound A35 is reacted with1-ethoxyvinyltributyltin (EVTB, available from Aldrich Chemical Co.) inthe presence of bis(triphenylphosphine)palladium(II)chloride intetrahydrofuran to provide, after acid work-up,4,4-dimethyl-7-acetyl-1-phenylthio-3,4-dihydronaphthalene (Compound C7).Compound C7 is subjected to a Horner Emmons reaction (as describedabove) with diethylcyanomethylphosphonate (available from AldrichChemical Co.) to provide3-[4,4-dimethyl-1-phenylthio-3,4-dihydronaphthalen-7-yl]but-2-en(E)-nitrile(Compound C8). Compound C8 is reduced with disobutyl aluminium hydrideto provide the corresponding aldehyde,3-[4,4-dimethyl-1-phenylthio-3,4-dihydronaphthalen-7-yl]but-2-en(E)-aldehyde(Compound C9). Compound C9 is subjected to still another Horner Emmonsreaction with the reagentdiethyl-(E)-3-ethoxycarbonyl-2-methylalkylphosphonate to yield ethyl7-[4,4-dimethyl-1-phenylthio-3,4,-dihydronaphthalen-7-yl]-3,7-dimethyl-hept-2(E),4(E), 6(E)trienoate (Compound C10). Compound C10 of the invention iswithin the scope of Formula 5.

[0259] In other preferred examples not shown in the schemes butdescribed in the Specific Examples, a sequence of reaction which isanalogous to the above-described reactions of Reaction Scheme 8 isconducted, starting with7-bromo-1(2H)-(propyliden-2-yl)-3,4-dihydro-4,4-dimethylnaphthalene(Compound A37), or with7-bromo-1(2H)-(phenylbenzylidenyl)-3,4-dihydro-4,4-dimethylnaphthalene(Compound C37) to provide further examples for compounds of theinvention, such as ethyl-7-[1(2H)-(propyliden-2-yl)-3,4-dihydro-4,4-dimethyl-naphthalen-7-yl]-3,7-dimethyl-hept-2(E),4(E),6(E)-trienoate(Compound C36) and ethyl7-[4,4-dimethyl-3,4-dihydro-1(2H)-phenylbenzylidenyl)-naphth-7-yl]-3,7-dimethyl-hepta-2(E),4(E),6(E)-trienoate(Compound C41). Compounds C36 and C41 of the invention are within thescope of Formula 3.

[0260] Compound C10 is converted by oxidation withmeta-chloroperoxybenzoic acid to the corresponding sulfone andsulfoxide, ethyl7-[4,4-dimethyl-1-phenylsulfonyl-3,4,-dihydronaphthalen-7-yl]-3,7-dimethyl-hept-2(E),4(E), 6(E)trienoate (Compound C11a) and ethyl7-[4,4-dimethyl-1-phenylsulfoxide-3,4,-dihydronaphthalen-7-yl]-3,7-dimethyl-hept-2(E),4(E), 6(E)trienoate (Compound C11b), which are also within the scope ofFormula 5.

[0261] Reaction Scheme 9 discloses the preferred method of synthesis ofa starting material from which certain examples for compounds of theinvention within the scope of Formula 6 are preferably made. Inaccordance with this scheme7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound G) isreacted with t-butylmagnesium chloride in tetrahydrofuran in thepresence of 1,3-dimethyl-3,4,5,6tetrahydro-2(H)-pyrimidinone (DMPU).Thereafter, the resulting intermediate tertiary alcohol is heated in thepresence of acid (p-toluenesulfonic acid) to give7-bromo-1-(1,1-dimethylethyl)-3,4-dihydro-4,4-dimethylnaphthalene(Compound C42). Compound C42 is reacted with 1-ethoxyvinyltributyltin(EVTB) in the presence of Pd(0) catalyst to yield after acidic work-up7-acetyl-1-(1,1-dimethylethyl)-3,4-dihydro-4,4-dimethylnaphthalene(Compound C43). Compound C43 is subjected to a sequence of reactions ofthe type described above in connection with Reaction Scheme 8, startingwith a Horner Emmons reaction with diethyl cyanomethylphosphonate, toeventually provide ethyl7-[4,4-dimethyl-3,4-dihydro-1-(1,1-dimethylethyl)-naphth-7-yl]-3,7-dimethyl-hepta-2(E),4(E),6(E)-trienoate(Compound C46). Compound C46 of the invention is within the scope ofFormula 6.

[0262] Reaction Scheme 10 discloses a preferred synthetic route tocertain examplary compounds of the invention where, with reference toFormulas 1-6 the Z group is —N═N— (azo) moiety. For the examples shownin this scheme the starting compound is3,4-dihydro-4,4-dimethyl-7-amino-naphthalen-1(2H)-one (Compound D9).Compound D9 is coupled with a nitroso compound of the formulaON—Y(R₂)-A-B, which in the herein shown example is ethyl4-nitrosobenzoate (available in accordance with the chemical literature;see Kagechika et al. J. Med. Chem. (1989) 32, 1098-1108). The couplingreaction is conducted in glacial acetic acid and yields ethyl4-[(5,6-dihydro-5,5-dimethyl-8(7H)-one-naphthalen-2-yl)azo]-benzoate(Compound D10). Compound D10 of the invention is within the scope ofFormula 2. Compound D10 is reacted in a Reformatsky reaction with ethylbromoacetate to provide (+/−) ethyl4-[(5,5-dimethyl-8-hydroxy-8-carbethoxymethyl-5,6,7,8-tetrahydronaphth-2-yl)azo]benzoate(Compound D1). Compound D1 of the invention is within the scope ofFormula 1. Dehydration of Compound D1 with dicyclohexylcarbodiimide andcuprous chloride in benzene provides the isomeric compounds ethyl4-[(5,5-dimethyl-8(7H)-(carbethoxymethylidenyl)-5,6-dihydronaphthalen-2-yl)azo]benzoate(Compound -D2a) and ethyl4-[(5,5-dimethyl-8(carbethoxymethyl)-5,6-dihydronaphthalen-2-yl)azo]benzoate(Compound D2b). Compound D2a of the invention is within the sope ofFormula 3, and Compound D2b is within the scope of Formula 6.

[0263] The “oxo” compound ethyl4-[(5,6-dihydro-5,5-dimethyl-8(7H-one-naphthalen-2-yl)azo]-benzoate(Compound D10) serves as starting material for reactions which lead tofurther compounds of the invention in accordance with syntheticmethodology that has been described above. More particularly, in theexamples shown in Reaction Scheme 10 Compound D10 is converted into theO-methyl oxime derivative ethyl 4-[(8(7H)-anti-(O-methyloxime)-5,5-dimethyl-5,6-dihydronaphthalen-2-yl)azo]benzoate (CompoundD3), into the “triflate” ethyl4-[(5,6-dihydro-5,5-dimethyl-8-(trifluoromethylsulfonyl)oxy-naphthalen-2-yl)azo]-benzoate(Compound D11) and is reduced to the secondary alcohol (+/−) ethyl4-[(5,5-dimethyl-8-hydroxy-5,6,7,8tetrahydronaphthalen-2-yl)azo]benzoate(Compound D5). The O-methyl oxime derivative (Compound D3) of theinvention is within the scope of Formula 4, the “triflate” Compound D11is in the scope of Formula 5, whereas the secondary alcohol Compound D5is within the scope of Formula 1.

[0264] The secondary alcohol, Compound D5 is further converted into themethoxymethyl derivative (+/−) ethyl4-[(5,5-dimethyl-8-(methoxymethyloxy)-5,6,7,8-tetrahydronaphthalen-2-yl)azo]benzoate(Compound D6) within the scope of Formula 1, and the “triflate” isreacted with thienyl lithium in the presence of ZnCl₂ and Pd(0) catalystto provide ethyl4-[(5,5-dimethyl-8-(2-thienyl)-5,6-dihydronaphthalen-2-yl)azo]benzoate(Compound D12).

[0265] Referring now to Reaction Scheme 11 a preferred example for thesynthesis of those compounds of the invention is described where, withreference to Formulas 1-6 the Z group is —CO—CR₁═CR₁—. As it will becomeapparent from the reaction scheme, these compounds are obtained as aresult of an aldol condensation between an appropriately substitutedtetrahydro or dihydronaphthalene ketone derivative and an aldehyde ofthe formula OCH—Y(R₂)A-B. In the example shown in Reaction Scheme 11 theexocyclic ketone function of3,4-dihydro-4,4-dimethyl-6-acetyl-naphthalen-1(2H)-one (Compound D14b)is reacted with ethylene glycol and acid to provide6-(2-methyl-1,3-dioxolan-2-yl)-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one(Compound D15) where one ketone function is protected. Compound D15 isthen reacted with ethyl bromoacetate in a Reformatsky reaction to give(+/−)6-(2-methyl-1,3-dioxolan-2-yl)]-1,2,3,4-tetrahydro-4,4-dimethyl-1-hydroxy-1-(carboethoxymethyl)-naphthlene(Compound D16). Treatment with acid of Compound D16 removes the1,3-dioxolanyl protecting group and also introduces a double bond intothe tetrahydronaphthalene nucleus, thus providing3,4-dihydro-4,4-dimethyl-1-(carbethoxymethyl)-6-acetyl-naphthalene(Compound D17).

[0266] An alternate method for obtaining dihydronaphthalene compoundshaving the 6-acetyl substituent and a substituent in the 1-position(attached to the vinylic carbon) is to react Compound D15 with sodiumbis(trimethylsilyl)amide and2-[N,N-bis(trifluoromethylsulfonyl)amino]-5-chloropyridine in an inertether type solvent, such as tetrahydrofuran, at low temperatures (−78°C. and 0° C.). As noted above in connection with an analogous “triflate”forming reaction, this reaction proceeds through a sodium saltintermediate which is usually not isolated. The overall reaction resultsin a trifluoromethylsulfonyloxy derivative, which is therafter reactedwith an organometal derivative, again in analogy to the precedingdescription of synthesizing compounds of Formula 6 from the “triflate”derivatives.

[0267] Returning now to the description of Reaction Scheme 11, CompoundD17 is reacted with 4-carboxybenzaldehyde in an aldol condensationreaction to give ethyl(E)-4-[3-(3,4-dihydro-4,4dimethyl-1-(carbethoxymethyl)-naphthalen-6-yl)-prop-1-en-3-one]benzoate(Compound D18). The just described aldol condensation reaction isconducted in the presence of base in an alcoholic solvent. Preferably,the reaction is conducted in methanol or ethanol in the presence ofsodium hydroxide. Those skilled in the art will recognize the aldolcondensation reaction of this example as a Claisen-Schmidt reaction.(See March: Advanced Organic Chemistry: Reactions, Mechanisms, andStructure, pp 694 695 McGraw Hill (1968). Examples of other reagentsanalogous to 4-carboxybenzaldehyde and suitable for the condensationreaction to introduce heterocyclic Y(R₂) groups into the compounds ofthe present invention 1) are: 5-carboxypyridine-2-carboxaldehyde,4-carboxypyridine-2-carboxaldehyde, 4-carboxythiophene-2-carboxaldehyde,5-carboxy-thiophene-2-carboxaldehyde, 4-carboxyfuran-2-carboxaldehyde,5-carboxyfuran-2-carboxaldehyde, 4-carboxyacetophenone,2-acetylpyridine-5-carboxylic acid, 2-acetylpyridine-4-carboxylic acid,2-acetyl-thiophene-4-carboxylic acid, 2-acetylthiophene-5-carboxylicacid, 2-acetylfuran-4-carboxylic acid, and 2-acetylfuran-5-carboxylicacid. The latter compounds are available in accordance with the chemicalliterature; see for example Decroix et al., J. Chem. Res.(S), 1978, 4,134; Dawson et al., J. Med. Chem., 1983×, 1282; and Queguiner et al.,Bull Soc. Chimique de France, 1969. No. 10, pp 3678-3683. Compound D18of the invention is within the scope of Formula 6.

[0268] To obtain further preferred examples of the compounds of theinvention where the Z group is —CO—CR₁═CR₁— the aldol condensationreaction shown in Reaction Scheme 11 is performed on the followingcompounds:

[0269]3,4-dihydro-4,4-dimethyl-6-acetyl-1-(1,1-dimethylethyl)naphthalene(Compound D19);

[0270]6-Acetyl-1(2H)-(propyliden-2-yl)-3,4-dihydro-4,4-dimethylnaphthalene(Compound D22);

[0271] (+/−)1-(methoxymethyloxy)-6-acetyl-1,2,3,4-tetrahydro-4,4-dimethyl-naphthalene(Compound D26); and

[0272] 6-Acetyl-1 (2H)—(O-methyloxime)-3,4-dihydro-4,4-dimethylnaphthalene (Compound D28)

[0273] to provide respectively the following examples of compounds ofthe invention:

[0274](E)-4-[3-(3,4-dihydro-4,4-dimethyl-1-(1,1-dimethyl-ethyl)naphth-6-yl)-prop-1-en-3-one]benzoicacid (Compound D20, Formula 6);

[0275](E)-4-[3-{1(2H)-(propyliden-2-yl)-3,4-dihydro-4,4-dimethylnaphthalen-6-yl}-prop-1-en-3-one]benzoicacid (Compound D23, Formula 3);

[0276](E)₄-[3-(1,2,3,4tetrahydro-4,4-dimethyl-1-(methoxymethyloxy)-naphthalen-6-yl)-prop-1-en-3-one]benzoicacid (Compound D27, Formula 1), and

[0277] (E)-4-[3-{1(2H)—(O-methyloxime)-3,4-dihydro-4,4-dimethylnaphthalen-6-yl}-prop-1-en-3-one]benzoicacid (Compound D29, Formula 4).

[0278] Reaction Scheme 12 discloses the presently preferred methods forsynthesizing preferred examples of compounds of the invention where withreference to Formulas 1-6 the Z group is —COO— or —CONH—. As is shown inthe scheme, 7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one(Compound G) is reacted with carbon monoxide in the presence ofpalladium(II)-bis(triphenylphosphine)chloride,1,3-bis(diphenylphosphino)-propane, DMSO, methanol and triethylamine toobtain the corresponding carboxylic acid methyl ester, methyl5,5-dimethyl-5,6-dihydro-naphthalen-8(7H)-one-2-carboxylate (CompoundE2), which is thereafter saponified to provide5,5-dimethyl-5,6-dihydro-naphthalen-8(7H)-one-2-carboxylic acid(Compound E3). Compound E3 is a free carboxylic acid which is reactedeither with compounds of the formula H₂N—Y(R₂)-A-B to provide compoundsof the invention where Z is —CONH—, or with compounds of the formulaHO—Y(R₂)-A-B to provide compounds of the invention where Z is —COO—.Those skilled in the art will recognize that these compounds of theinvention are amide and ester compounds, is respectively. Generallyspeaking several known methods for amide and ester formation may beemployed for their synthesis from Compound E3 or analogous carboxylicacid compounds. For example, Compound E3 or analogous carboxylic acidcompounds can be converted into the acid chloride by known methods andthereafter reacted with the amines or esters of formula H₂N—Y(R₁)-A-B orformula HO—Y(R₂)-A-B respectively. The presently preferred method forsynthesis, however utilizes the reagents1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl) and4-N,N-dimethylaminopyridine in an aprotic solvent for the amide or esterformation. Those skilled in the art will also recognize that thecompounds of formula H₂N—Y(R₂)-A-B and formula HO—Y(R)-A-B are aromaticor heteroaromatic amines or hydroxyl derivatives, which can be obtainedin accordance with the state-of-the-art.

[0279] Referring now back to Reaction Scheme 12 that describes certainpreferred specific examples,5,5-dimethyl-5,6-dihydro-naphthalen-8(7H)-one-2-carboxylic acid(Compound E3) is reacted in the presence of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl) and4-(dimethylamino)pyridine in methylene chloride to give ethyl4-[(5,5-dimethyl-8(7H)-one-5,6-dihydronaphthalen-2-yl)carboxamido]benzoate(Compound 28). Compound 28 of the invention is in the scope of Formula2. Reaction Scheme 12 discloses its conversion by reactions of the typedescribed above, to ethyl4-[(5,5-dimethyl-8(7H)-anti-(O-methyloxime)-5,6-dihydronaphthalen-2-yl)carboxamido]benzoate(Compound E30, Formula 4) and (+/−)4-[(5,5-dimethyl-8-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)carboxamido]benzoicacid (Compound E32, Formula 1). Compound E32 is converted to themethoxymethyl derivative (+/−) ethyl4-[(5,5-dimethyl-8-(O-methoxymethyl)-5,6,7,8-tetrahydronaphthalen-2-yl)carboxamido]benzoate(Compound E34) within the scope of Formula 1. Each of these amidecompounds can have their respective COOEt group saponified to providethe free carboxylic acid or its salt.

[0280] Referring still to Reaction Scheme 12, methyl5,5-dimethyl-5,6-dihydro-naphthalen-8(7H)-one-2-carboxylate (CompoundE2) is converted, under conditions described above for analogousreactions, into the trifluoromethylsulfonyl (“triflate”) derivative,methyl5,5-dimethyl-5,6-dihydro-8-(trifluoromethylsulfonyl)oxy-naphthalene-2-carboxylate (Compound E4). Compound E4 serves as an importantintermediate for the synthesis of compounds within the scope of Formula6. In the preferred examples shown in the reaction scheme, Compound E4is reacted with the lithium derivative of thiophene in the presence ofZnCl₂ and Pd(0) catalyst to provide the thienyl substituted carboxylicacid methyl ester, (Compound E5). The latter compound is saponified togive 5,5-dimethyl-5,6-dihydro-8-(2-thienyl)-naphthalene-2-carboxylicacid (Compound E6). Compound E6 is coupled with ethyl 4-aminobenzoate togive ethyl4[[(5,5-dimethyl-5,6dihydro-8-(2-thienyl)-naphthalen-2-yl)carboxamido]-benzoate(Compound E7), and with ethyl 94-hydroxybenzoate to provide ethyl4-[[(5,5-dimethyl-5,6-dihydro-8-(2-thienyl)-naphthalen-2-yl)carbonyl]oxy]-benzoate(Compound E9). Compounds E7 and E9 of the invention are within the scopeof Formula 6.

[0281] As it will be readily recognized in the art, the free carboxylicacid derivatives of the invention could not be obtained (or could beobtained only with difficulty) from the carbonyloxy compounds of thepresent invention by a process of saponification of the ester compoundssuch as Compound E9. However, the above-mentioned free carboxylic acids,such as4-[[(5,5-dimethyl-5,6-dihydro-8-(2-thienyl)-naphthalen-2-yl)carbonyl]oxy]-benzoicacid (Compound E11) can be obtained from the corresponding2-(trimethylsilyl)ethyl esters (such as 2-(trimethylsilyl)ethyl4-[[(5,5-dimethyl-5,6-dihydro-8-(2-thienyl)-naphthalen-2-yl)carbonyl]oxy]-benzoate, (Compound E10) by treatmentwith tetrabutylammonium fluoride. Compound E10 and like compounds can beobtained by coupling reactions of the type described above, utilizing,for example, 2-trimethylsilylethyl 4-hydroxybenzoate. The latterreactions are not shown in Reaction Scheme 12 but specific examples aredescribed below.

[0282] 5,5-Dimethyl-5,6-dihydro-naphthalen-8(7H)-one-2-carboxylic acid(Compound E3) is also coupled with ethyl 4hydroxybenzoate to provideethyl4-[[(5,5-dimethyl-8(7H)-one-5,6dihydronaphthalen-2-yl)carbonyl]oxy]benzoate(Compound E44) within the scope of Formula 2. Compound E44 is subjectedto a Reformatsky reaction with ethyl bromoacetate to yield (+/−) ethyl4-[[(5,5-dimethyl-8-hydroxy-8-(carbethoxy)-5,6,7,8-tetrahydronaphthalen-2-yl)carbonyl]oxy]benzoate(Compound E54). Although the following reactions are not shown in thescheme, an additional preferred example of compounds of the invention isobtained when Compound E44 is reduced with sodium borohydride to giveethyl4-[[(5,5-dimethyl-5,6,7,8-tetrahydro-8-hydroxy-naphthalen-2-yl)carbonyl]oxy]-benzoate(Compound E40). The latter is converted into tetrahydropyranylderivatives (within the scope of Formula 1) as is disclosed in detail inthe Specific Examples.

[0283] To obtain still more specific examples for the compounds of theinvention where the Z group is —COO— or —CONH—7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound G) issubjected to a Reformatsky reaction with ethyl bromoacetate, and theresulting (+/−) ethyl2-(1-hydroxy-1,2,3,4-tetrahydro-4,4-dimethyl-7-bromo-naphthalen-1-yl)acetate(Compound 47) is subjected to the series of reactions shown in ReactionScheme 12. These compounds, although not specifically shown in thescheme, are disclosed in detail in the appended Specific Examples.

[0284] Reaction Scheme 13 discloses examples for the synthesis ofseveral preferred compounds of the invention within the scope of Formula3. The reactions shown in this scheme are analogous to the reactionsdisclosed in the foregoing description and reaction schemes andtherefore will be readily understood by those skilled in the art and donot require further explanation here. A detailed experimentaldescription for the preparation of compounds shown in this scheme isprovided in the description of the Specific Examples. The same appliesto Reaction Scheme 14, which discloses examples for the synthesis ofseveral preferred compounds of the invention within the scope of Formula5.

[0285] Compounds of the invention where with reference to the Formulas1-6 the Z group is —N(O)═N— or —N═N(O)— can be prepared by oxidation ofcompounds where the Z group is —N═N—. A suitable oxidizing agent forthis purpose is meta-chloroperoxybenzoic acid; typically both isomers ofthe azoxy compounds are formed in reactions using this agent.

[0286] Compounds of the present invention where with reference toFormula 1-6, Z is —OCO—, NR₁CO, as well as the corresponding thioesterand thioamide analogs, can be prepared from the intermediates having abromo function on the aromatic portion of the tetrahydronaphthalene ordihydronaphthalene nucleus, for example such as Compounds G, H, A35,A37, B15 and C42. In these compounds the bromo function is replaced withan amino or hydroxyl group, in analogy to the teachings of U.S. Pat.Nos. 5,324,744, the specification of which is expressly incorporatedherein by reference.

[0287] Compounds of the present invention where with reference toFormula 1-6, Z is —N═CR₁— or —CR₁═N— will be readily recognized by thoseskilled in the art as Schiff bases. These compounds can be made byreaction between a primary amine and aldehyde or ketone. In order toobtain these compounds where the Z is —N═CR₁— an amine of the structurewhere the NH₂ group is attached to the aromatic portion of thetetrahydronaphthalene or dihydronaphthalene nucleus, is reacted with analdehyde or ketone of the structure OCR₁—Y(R₂)-A-B. An example for suchan amine is Compound D9. Schiff bases of the structure where Z is—CR₁═N— can be obtained by reaction of an amine of the formulaNH₂—Y(R₁)-A-B with an aldehyde or ketone where the aldehyde or ketonefunction is attached to the aromatic portion of thetetrahydronaphthalene or dihydronaphthalene nucleus. Compounds D14a andD14b serve as examples.

[0288] Compounds of the present invention where with reference toFormula 1-6, the X₁ group is [C(R₁)₂]_(n) and n is zero (0), can be madestarting with 6-bromo-indan-1-one (or an appropriately subtitutedderivative). In these synthetic schemes 6-bromo-indan-1-one is used inanalogy to 7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H-one (CompoundG) as a starting material. 6-bromo-3,3-dimethyl-indan-1-one is availableaccordance with the chemical literature. (See Smith, J. G.,; Massicotte,M. P. Org. Prep. Proced. Int. 1978, 10 123-131.)

[0289] Compounds of the invention where with reference to Formula 1-6,the X₁ group is [C(R₁)₂]_(n) and n is 2 can be made from8bromo-2,3,4,5-tetrahydro-5,5-dimethyl-1-(2H)-suberan-one (Compound F7)which is used as a starting material in analogy to Compound G. CompoundF7 can be made in accordance with the reaction sequence shown inReaction Scheme 15. As is shown in the scheme,(3-bromophenyl)acetaldehyde (Compound F1) is subjected to a Wittigreaction to obtain a 5 carbon chain attached to the aromatic nucleus,and the resulting Compound F2 is hydrogenated and subjected to Jonesoxidation followed by esterification, to provide methyl(3-bromophenyl)-pentanoate (Compound F4). Compound F4 is reacted with aGrignard reagent to provide a tertiary alcohol (Compound F5), which iscyclized to provide 8-bromo-2,3,4,5-tetrahydro-5,5-dimethyl-suberan(Compound F6). Compound F6 is oxidized with CrO₃ to yield8-bromo-2,3,4,5-tetrahydro-5,5-dimethyl-1-(2H)-suberan-one (CompoundF7).

SPECIFIC EXAMPLES

[0290] Ethyl (4-bromophenyl)acetate (Compound A)

[0291] A solution of 43 g (200 mmol) of 4-bromophenylacetic acid and 0.2g of conc. H₂SO₄ in 470 ml of ethanol was refluxed for 16 hours. Thereaction mixture was cooled to ambient temperature, stirred with 6 g ofsolid K₂CO₃ for 30 minutes and then filtered. The filtrate wasconcentrated in vacuo, diluted with Et₂O (200 ml), washed with 10%aqueous NaHCO₃ (10 ml) and brine (10 ml), dried over MgSO₄ andconcentrated in vacuo to give the title compound as a colorless oil.

[0292] PMR (CDCl₃): δ 1.25 (3H, t, J=7.0 Hz), 3.56 (2H, s), 4.15 (2H, q,J=7.0 Hz), 7.16 (2H, d, J=8.4 Hz), 7.45 (2H, d, J=8.4 Hz).

[0293] Ethyl (3-bromophenyl)acetate (Compound B)

[0294] Employing the same general procedure as for the preparation ofethyl (4-bromophenyl)acetate (Compound A), 100 g (463 mmol) of3-bromophenylacetic acid was converted into the title compound (yellowoil) using 2 g of conc. H₂SO₄ and 500 ml of ethanol.

[0295] PMR (CDCl₃): δ 1.26 (3H, t, J=7.0 Hz), 3.56 (2H, s), 4.16 (2H, q,J=7.0 Hz), 7.16-7.26 (2H, m), 7.38-7.46 (2H, m).

[0296] Ethyl 4-(4-bromophenyl)butanoate (Compound C)

[0297] To a cold solution (−78° C.) of 15 g (62 mmol) of ethyl(4-bromophenyl)acetate (Compound A) in 150 ml of C12 was added dropwise(over a span of 1 hour) 65 ml (65 mmol) of diisobutylaluminum hydride(DIBAL-H, 1M solution in hexane). After the DIBAL-H addition wascomplete, the reaction was stirred at −78° C. for an additional hour.The reaction was quenched by the dropwise 13.addition of methanol (10ml), followed by water (10 ml) and 10% HCl (40 ml). The mixture was thenwarmed to 0° C., stirred for 10 minutes and then washed with water (15ml), 10% aqueous NaHCO₃ (10 ml) and brine (10 ml). The organic phase wasdried over MgSO₄ and the solvent distilled off at ambient temperature togive crude (4-bromophenyl)acetaldehyde. To a cold solution (0° C.) ofthis crude aldehyde in 150 ml of CH₂Cl₂ was added a solution of 26 g(74.6 mmol) of (carbethoxymethylene)triphenylphosphorane in 50 ml ofCH₂Cl₂. The mixture was stirred for 16 hours, concentrated in vacuo andpurified by flash chromatography (silica, 10% EtOAc-hexane) to giveethyl 4-(4-bromophenyl)but-2-enoate as a mixture of E:Z isomers. Thisisomeric mixture was dissolved in 150 ml of EtOAc and hydrogenated over1 g of 10% Pd/C for 6 hours. The catalyst was filtered off and thefiltrate concentrated in vacuo to give the title compound as a whitesolid.

[0298] PMR (CDCl₃): δ 1.26 (3H, t, J=7.1 Hz), 1.88-1.99 (2H, m), 2.31(2H, t, J=7.5 Hz), 2.61 (2H, t, J=7.5 Hz), 4.28 (2H, q, J=7.1 Hz), 7.05(2H, d, J=8.4 Hz), 7.40(2H, d, J=8.4 Hz).

[0299] Ethyl 4-(3-bromophenyl)butanoate (Compound D)

[0300] Employing the same general multistep preparation as for ethyl4-(4-bromophenyl)butanoate (Compound C), 60 g (246 mmol) of ethyl(3-bromophenyl)acetate (Compound B) was converted into the titlecompound (oil) using 255 ml (255 mmol) of diisobutylaluminum hydride(DIBAl—H, 1M in hexane), 85.8 g (250 mmol) of(carbethoxymethylene)triphenylphosphorane and 1.7 g of 10% Pd/C.

[0301] PMR (CDCl₃): δ 1.26 (3H, t, J=7.1 Hz), 1.89-2.00 (2H, m), 2.31(2H, t, J=7.5 Hz), 2.63 (2H, t, J=7.2 Hz), 4.15 (2H, q, J=7.1 Hz),7.10-7.35 (4H, m).

[0302] 5-(3-bromophenyl)-2-methylpentan-2-ol (Compound E)

[0303] To a cold solution (0° C.) of 17 g (63 mmol) of ethyl4-(3-bromophenyl)butanoate (Compound D) in 40 ml of THF was added 63 ml(189 mmol) of methylmagnesium bromide (3.0M solution in THF). Thereaction was stirred at 0° C. for 2 hours, quenched by the slow additionof ice cold water (30 ml) followed by 10% HCl (30 ml) and then extractedwith Et₂O (4×60 ml). The combined organic layer was washed with 10%aqueous NaHCO₃ (10 ml), water (10 ml) and brine (10 ml), dried overMgSO₄ and concentrated in vacuo. purification by Kugelrohr distillationgave the title compound as a colorless oil.

[0304] PMR (CDCl₃): δ 1.20 (6H, s), 1.43-1.55 (2H, m), 1.62-1.78 (2H,m), 2.60 (2H, t, J=6.0 Hz), 7.10-7.41 (4H, m).

[0305] 6-Bromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound F)

[0306] 15.0 g (58.3 mmol) of 5-(3-bromophenyl)-2-methylpentan-2-ol(Compound E) was cooled to 0° C. and then 2.8 ml of conc. H₂SO₄ wasadded. The mixture was stirred for 2.5 hours, diluted with water (20 ml)and extracted with Et₂O (3×40 ml). The combined organic layers werewashed with water, sat. aqueous NaHCO₃ and brine, dried over MgSO₄ andconcentrated in vacuo. Purification by Kugelrohr distillation gave thetitle compound as a colorless oil.

[0307] PMR (CDCl₃): δ 1.25 (6H, s), 1.61-1.66 (2H, m), 1.74-1.82 (2H,m), 2.73 (2H, t, J=6.0 Hz), 7.16-7.26 (3H, m).

[0308] 7-Bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound G)

[0309] To a cold mixture (0° C.) of 209 g (200 mmol) of chromiumtrioxide, 100 ml (1.06 mmol) of acetic anhydride and 200 ml (3.5 mmol)of acetic acid was added a solution of 10 g (41.8 mmol) of6-bromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound F) in 125ml of benzene. The reaction mixture was stirred for 1 hour, quenchedwith ice cold water and extracted with Et₂O (3×100 ml). The organiclayer was dried over MgSO₄, concentrated in vacuo, and purified bycolumn chromatography (silica, 10% EtOAc-hexane) to give the titlecompound as a white solid.

[0310] PMR (CDCl₃): δ 1.28 (6H, s), 2.01 (2H, t, J=6.0 Hz), 2.72 (2H, t,J=6.0 Hz), 7.31 (1H, d, J=9.0H), 7.61 (1H, dd, J=3.0, 9.0 Hz), 8.11 (1H,d, J=3.0 Hz).

[0311] 6-Bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound H)

[0312] Employing a published procedure (Mathur, N. C.; Snow, M. S.Young, K. M.; and Pincock, J. A. Tetrahedron, 41, 1509-1516 (1985)),ethyl 4-(4-bromophenyl)butanoate (Compound C) was converted into thetitle compound. Alternatively, the title compound can be obtained usingsimilar reactions that were used to convert ethyl4-(3-bromophenyl)butanoate (Compound D) into7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound G)

[0313] Ethyl(E)-4-[2-(5,6-dihydro-5,5-dimethyl-naphthalen-8(7H)-one-2-yl)ethenyl]-benzoate

[0314] (Compound A2)

[0315] To a solution of 520.0 mg (2.00 mmol) of3,4-dihydro-4,4-dimethyl-7-bromo-naphthalen-1(2H)-one (Compound G), and510.0 mg (2.90 mmol) of ethyl 4-vinylbenzoate in 4.0 mL of triethylamine(degassed by sparging with argon for 25 minutes), was added 124.0 mg(0.40 mmol) of tris(2-methylphenyl) phosphine, followed by 44.0 mg (0.20mmol) of palladium(II)acetate. The resulting solution was heated to 95°C. for 2.5 h, cooled to room temperature, and concentrated under reducedpressure. Purification by column chromatography (10% EtOAc/hexanes)afforded the title compound as a colorless solid.

[0316]¹H NMR (CDCl₃): δ 1.41 (t, J=7.1 Hz, 3H), 1.41 (s, 6H), 2.04 (t,J=6.5 Hz, 2H), 2.76 (t, J=6.5 Hz, 2H), 4.39 (q, J=7.1 Hz, 2H), 7.20 (s,2H), 7.45 (d, J=8.2 Hz, 1H), 7.57 (d, J=8.4 Hz, 2H), 7.69 dd, J=2.0, 8.2Hz, 1H), 8.03 (d, J=8.4 Hz, 2H), 8.19 (d, J=2.0 Hz, 1H).

[0317]E)-4-[2-(5,6,7,8-tetrahydro-5,5-dimethyl-8-oxo-2-naphthalenyl)ethenyl]-benzoicAcid (Compound A2a)

[0318] Employing the same general procedure as for the preparation of(E)-4-[2-(5,6,7,8-tetrahydro-5,5-dimethyl-8-anti-(O-methyloxime)-2-naphthalenyl)ethenyl]-benzoic acid

[0319] Compound A4) 110 mg (0.32 mmol) of ethyl(E)-4-[2-(5,6,7,8-tetrahydro-5,5-dimethyl-8-oxo-2-naphthalenyl)ethenyl]-benzoate(Compound A2) was converted into the title compound using 1.0 mL (1.5mmol) of LiOH (1.5 M aqueous solution) and 0.5 mL of methanol.

[0320] 1H NMR (DMSO) δ 1.36 (s, 6H), 1.96 (t, J=6.7 Hz, 3H), 2.69 (t,J=6.7 Hz, 2H), 7.35 (d, J=16.4 Hz, 1H), 7.49 (d, J=16.4 Hz, 1H), 7.58(d, J=8.4 Hz, 1H), 7.74 (d, J=8.4 Hz, 2H), 7.89 (overlapping d, 3H),8.05 (s, 1H).

[0321] Ethyl (E)-4-[2-(5,5-dimethyl-5,6,-dihydro-8(7H)-anti-(O-methyloxime)-naphthalen-2-yl)ethenyl]-benzoate (Compound A3)

[0322] A solution of 298 mg (0.85 mmol) of ethyl(E)-4-[2-(5,5-dimethyl-5,6,-dihydro-naphthalen-8(7H)-one-2-yl)ethenyl]-benzoate(Compound A2), 290 mg (3.4 mmol) of methoxylamine hydrochloride and 610mg (4.5 mmol) of sodium acetate in 7.0 mL of EtOH and 5.0 mL oftetrahydrofuran was stirred at ambient temperature for 96 h and refluxedfor 3 h. An additional 0.24 g (1.8 mmol) of methoxylamine hydrochloridewas added and the mixture refluxed for another 1 h. The mixture wasconcentrated in vacuo, the residue was diluted with water and extractedwith EtOAc (2×). The combined organic layer was dried over MgSO₄, andconcentrated in vacuo. The crude material was purified by flashchromatography (silica, 5% ethyl acetate in hexanes) to afford the titlecompound as a yellow oil.

[0323]¹H NMR (CDCl₃): δ 1.30 (s, 6), 1.41 (t, J=7.1 Hz, 3H), 1.73 (t,J=6.9 Hz, 2H), 2.80 (t, J=6.9 Hz, 2H), 4.04 (s, 3H), 4.39 (q, J=7.1 Hz,2H), 7.13 (d, J=16.4 Hz, 1H), 7.22 (d, J=16.4 Hz, 1H), 7.36 (d, J=8.2Hz, 1H), 7.50 (dd, J=2.0, 8.2 Hz, 1H), 7.57 (d, J=8.4 Hz, 2H), 8.03 (d,J=8.4 Hz, 2H), 8.11 (d, J=2.0 Hz, 1H).

[0324] (E)-4-[2-(5,5-Dimethyl-5,6,-dihydro-8(7H)-anti-(O-methyloxime)-naphthalen-2-yl)ethenyl]-benzoic Acid (Compound A4)

[0325] To a solution of 183 mg (0.48 mmol) of ethyl(E)-4-[2-(5,5-dimethyl-5,6,-dihydro-8(7H)-anti-(O-methyloxime)-naphthalen-2-yl)ethenyl]-benzoate (Compound A3) in 4.0 mL oftetrahydrofuran and 1.0 mL of methanol was added 1.0 mL (2.4 mmol) ofLiOH (2.4 M aqueous solution). The mixture was stirred at ambienttemperature for 19 h, and concentrated in vacuo. The residue was dilutedwith water and acidified to pH 1 with 10% HCl, and extracted with ethylacetate (2×). The organic phase was washed with brine, dried with MgSO₄and concentrated in vacuo. Recrystallization of the crude product usingacetonitrile afforded the title compound as white crystals.

[0326]¹H NMR (DMSO-D₆): δ 1.24 (s, 6H), 1.66 (t, J=6.6 Hz, 2H), 2.72 (t,J=6.6 Hz, 2H), 3.95 (s, 1H), 7.26 (d, J=16.5 Hz, 1H), 7.44 (d, J=8.2 Hz,1H), 7.44 (d, J=16.5 Hz, 1H), 7.67 (d, J=8.2 Hz, 1H), 7.74 (d, J=8.1 Hz,2H), 7.92 (d, J=8.1 Hz, 2H), 8.01 (s, 1H).

[0327] Ethyl (E)-4-[2-(5,5-dimethyl-5,6,-dihydro-8(7H)-anti-(O-ethyloxime)-naphthalen-2-yl)ethenyl]-benzoate (Compound A5)

[0328] Employing the same general procedure as for the preparation ofethyl (E)-4-[2-(5,5-dimethyl-5,6,-dihydro-8(7H)-anti-(O-methyloxime)-naphthalen-2-yl)ethenyl]-benzoate (Compound A3) 146 mg (0.42mmol) of ethyl (E)-4-[2-(5,5-dimethyl-5,6,dihydronaphthalen-8(7H)-one-2-yl)ethenyl]-benzoate (Compound A2) wasconverted into the title compound (white solid) using 167 mg (1.7 mmol)of ethoxylamine hydrochloride, 337 mg (2.5 mmol) of sodium acetate, 5.0mL of EtOH and 1.0 mL of tetrahydrofuran.

[0329]¹H NMR (CDCl₃): δ 1.28 (s, 6H), 1.35 (t, J=7.1 Hz, 3H), 1.39 (t,J=7.1 Hz, 3H), 1.71 (t, J=6.9 Hz, 2H), 2.80 (t, J=6.9 Hz, 2H), 4.27 (q,J=7.1 Hz, 2H), 4.37 (q, J=7.1 Hz, 2H), 7.11 (d, J=16.4 Hz, 1H), 7.21 (d,J=16.4 Hz, 1H), 7.34 (d, J=8.2 Hz, 1H), 7.48 (dd, J=1.9, 8.2 Hz, 1H),7.55 (d, J=8.4 Hz, 2H), 8.01 (d, J=8.4 Hz, 2H), 8.11 (d, J=1.9 Hz, 1H).

[0330] (E)-4-[2-(5,5-Dimethyl-5,6,-dihydro-8(7H)-anti-(O-ethyloxime)-naphthalen-2-yl)ethenyl]-benzoic Acid (Compound A6)

[0331] Employing the same general procedure as for the preparation of(E)-4-[2-(5,5-dimethyl-5,6,-dihydro—8(7H)-anti-(O-methyloxime)-naphthalen-2-yl)ethenyl]-benzoic acid (Compound A4) 81 mg (0.21mmol) of ethyl (E)-4-[2-(5,5-dimethyl-5,6-dihydro-8(7H)-anti-(O-ethyloxime)-naphthalen-2-yl)ethenyl]-benzoate (Compound A5) was convertedinto the title compound (white solid) using 1.0 mL (1.8 mmol) of LiOH(1.8 M aqueous solution).

[0332]¹H NMR (Acetone-D₆): δ 1.30 (s, 6H), 1.31 (t, J=7.1 Hz, 3H), 1.73(t, J=6.9 Hz, 2H), 2.78 (t, J=6.9 Hz, 2H), 4.23 (q, J=7.1 Hz, 2H), 7.30(d, J=16.4 Hz, 1H), 7.41 (d, J=16.4 Hz, 1H), 7.41 (d, J=8.2 Hz, 1H),7.66 (dd, J=1.9, 8.2 Hz, 1H, 7.76 (d, J=8.4 Hz, 2H), 8.03 (d, J=8.4 Hz,2H), 8.15 (d, J=1.9 Hz, 1H).

[0333] Ethyl(E)-4-[2-(5,5-dimethyl-5,6,-dihydro-8(7H)-anti-(oxime)-naphthalen-2-yl)ethenyl]-benzoate(Compound A7)

[0334] Employing the same general procedure as for the preparation ofethyl (E)-4-[2-(5,5-dimethyl-5,6,-dihydro-8(7H)-anti-(O-methyloxime)-naphthalen-2-yl)ethenyl]-benzoate (Compound A3) 190 mg (0.55mmol) of ethyl(E)-4-[2-(5,5-dimethyl-5,6-dihydronaphthalen-8(7H)-one-2-yl)ethenyl]-benzoate(Compound A2) was converted into the title compound using 152 mg (1.7mmol) of hydroxylamine hydrochloride, 430 mg (3.2 mmol) of sodiumacetate, 6.0 mL of EtOH and 1.0 mL of tetrahydrofuran.

[0335]¹H NMR (CDCl₃): δ 1.32 (s, 6H), 1.41 (t, J=7.1 Hz, 3H), 1.77 (t,J=7.0 Hz, 2H), 2.91 (t, J=7.0 Hz, 2H), 4.39 (q, J=7.1 Hz, 2H), 7.13 (d,J=16.4 Hz, 1H), 7.20 (d, J=16.4 Hz, 1H), 7.39 (d, J=8.2 Hz, 1H), 7.49(m, J=1.8 Hz, 1H), 7.53 (d, J=8.4 Hz, 2H), 8.02 (d, J=8.4 Hz, 2H), 8.08(d, J=1.8 Hz, 1H), 8.48 (s, 1H).

[0336](E)-4-[2-(5,5-Dimethyl-5,6,-dihydronaphthalen-8(7H)-anti(oxime)-2-yl)ethenyl]-benzoicAcid (Compound A8)

[0337] Employing the same general procedure as for the preparation of(E)-4-[2-(5,5-dimethyl-5,6,-dihydro-8(n-anti-(O-methyloxime)-naphthalen-2-yl)ethenyl]-benzoic acid (Compound A4) 104 mg (0.29mmol) of ethyl(E)-4-[2-(5,-dimethyl-5,6,-dihydro-8(7H)-and-(one)-naphthalen-2-yl)ethenyl]-benzoate(Compound A7) was converted into the title compound using 1.0 mL (1.5mmol) of LiOH (1.5 M aqueous solution).

[0338]¹H NMR (DMSO-D₆): δ 1.24 (s, 6H), 1.66 (t, J=6.7 Hz, 2H, 1.71 (t,J=6.7 Hz, 2H), 7.23 (d, J=16.5 Hz, 1H, 7.41 (d, J=8.3 Hz, 1H), 7.42 (d,J=16.5 Hz, 1H), 7.62 (dd, J=1.7, 8.3 Hz, 1H), 7.73 (d, J=8.5 Hz, 2H),7.92 (d, J=8.5 Hz, 2H), 8.03 (d, J=1.7 Hz, 1H).

[0339] Ethyl(E)-4-[2-(5,6-dihydro-5,5-dimethyl-8-(trifluoromethylsulfonyl)oxy-naphthalen-2-yl)ethenyl]-benzoate(Compound A9)

[0340] To a cold (−78° C.) solution of 440.0 mg (2.40 mmol) of sodiumbis(trimethylsilyl)amide in 10.0 mL of THF was added 700.0 mg (2.00mmol) of ethyl(E)-4-[2-(5,6-dihydro-5,5-dimethyl-naphthalen-8(7H)-one-2-yl)ethenyl]-benzoate(Compound A2) as a solution in 25.0 mL of THF. After stirring at −78° C.for 1.5 h, 960.0 mg (2.40 mmol) of 2[N,N-bistrifloromethylsulfonyl)amino]-5-chloropyridine was added in one portion.After 30 min, the solution was warmed to 0° C. and stirred for 3 h. Thereaction was quenched by the addition of saturated aqueous NH₄C1, andextracted with EtOAc. The combined extracts were washed with 5% aqueousNaOH, dried (NaSO₄), and the solvents removed under reduced pressure.The title compound was isolated as a colorless solid after columnchromatography (7% EtOAc/hexanes).

[0341]¹H NMR (CDCl₃): 31.32 (s, 6H), 1.41 (t, J=7.1 Hz, 3H), 2.43 (d,J=4.9 Hz, 2H), 4.39 (q, J=7.1 Hz, 2H), 6.00 (t, J=4.9 Hz, 1H), 7.10 (d,J=16.4 Hz, 1H), 7.20 (d, J=16.4 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 7.49(d, J=8.0 Hz, 1H), 7.52 (s, 1), 7.57 (d, J=8.4 Hz, 2H), 8.04 (d, J=8.4Hz, 1H).

[0342] Ethyl(E)₄-[2-(5,5-dimethyl-8-(thiazol-2-yl)-5,6-dihydronaphthalen-2-yl)ethenyl]-benzoate(Compound A10)

[0343] To a cold (−78° C.) solution of thiazole (0.38 g (0.10 mL, 1.4mmol) in THF (2.0 mL) was added n-butyl lithium (1.6 M solution inhexanes, 0.5 mL, 0.8 mmol) and stirred for 30 min. To this solution wasadded a 0.176 g (1.3 mmol) of zinc chloride in 3.0 mL of tetrahydrofuranand stirred for 45 min. The resulting turbid solution was transferred,via cannula, to a flask containing a mixture of 0.17 g (0.35 mmol) ofethyl(E)-4-[2-(5,5-dimethyl-8-(trifluoromethylsulfonyl)oxy-5,6-dihydronaphthalen-2-yl)ethenyl]benzoate (Compound A9) and 15 mg (0.01 mmol) oftetrakis(triphenylphosphine)palladium(0) in 3.0 mL of tetrahydrofuran.The reaction mixture was stirred for 1 h at ambient temperature and 1.5h at 55° C. The reaction mixture was treated with aqueous NH₄Cl, andextracted with EtOAc (2×). The combined organic layer was washed withbrine and dried (MgSO₄). The solvent was removed under reduced pressureand the crude product was purified by flash chromatography (silica, 20%ethyl acetate in hexane) to afford the title compound as a white solid.

[0344]¹H NMR (CDCl₃): δ 1.34 (s, 6H), 1.40 (t, J=7.1 Hz, 3H), 2.41 (d,J=4.9 Hz, 2H), 4.37 (q, J=7.1H, 2H), 6.56 (t, J=4.9 Hz, 1H), 7.03 (d,J=16.4 Hz, 1H), 7.18 (d, J=16.4 Hz, 1H), 7.34 (d, J=3.4 Hz, 1H), 7.38(d, J=8.1 Hz, 1H), 7.48 (dd, J=1.8, 8.4 Hz, 1H), 7.53 (d, J=8.4 Hz, 2H),7.86 (d, J=1.8 Hz, 1H), 7.93 (d, J=3.4 Hz, 1H), 8.00 (d, J=8.4 Hz, 2H).

[0345](E)-4-[2-(-5,5-Dimethyl-8-(thiazol-2-yl)-5,6-dihydronaphthalen-2-yl)ethenyl]-benzoicAcid (Compound A12)

[0346] Employing the same general procedure as for the preparation of(E)-4-(2-(5,5-dimethyl-5,6,-dihydro-8(7H-anti-(O-methyloxime)-naphthalen-2-yl)ethenyl]-benzoic acid (Compound A4), 20 mg (0.05mmol) of ethyl(E)-4-[2-(5,6-dihydro-5,5-dimethyl-8-(thiazol-2-yl)-naphthalen-2-yl)ethenyl]-benzoate(Compound A10) was converted into the title compound (white solid).

[0347]¹H NMR (CDCl₃): δ 1.28 (s, 6H), 2.39 (d, J=4.9 Hz, 2H), 6.63 (t,J=4.9 Hz, 1H), 7.15 (d, J=16.4 Hz, 1H), 7.36 (d, J=16.4 Hz, 1H), 7.43(d, J=8.2 Hz, 1H), 7.63 (d, J=8.2 Hz, 1H), 7.70 (d, J=8.2 Hz, 2H), 7.77(d, J=3.3 Hz, 1H), 7.90 (m, J=8.2 Hz, 3H), 7.97 (d, J=3.3 Hz, 1H).

[0348] Ethyl(E)-4-[2-(-5,5-dimethyl-8-(2-thienyl)-5,6-dihydronaphthalen-2-yl)ethenyl]-benzoate(Compound A13)

[0349] A solution of lithiothiophene was prepared by the addition of0.10 g (0.095 mL, 1.2 mmol) of thiophene to a cold solution (−78° C.) of0.61 g (0.90 mL, 1.4 mmol, 1.6 M in hexanes) of n-butyl lithium in 2.0mL of tetrahydrofuran. The solution was stirred at −78° C. for 35 minand then a solution of 0.158 g (1.2 mmol) of zinc chloride in 2.0 mL oftetrahydrofuran was added. The resulting solution was stirred at −78° C.to room temperature for 1 h and then the organozinc was added viacannula to a mixture of 0.212 g (0.44 mmol) of ethyl(E)-4-[2-(5,5-dimethyl-8-(trifluoromethylsulfonyl)oxy-5,6-dihydronaphthalen-2-l)ethenyl]benzoate (Compound A9) and 18 mg (0.016 mmol) oftetrakis(triphenylphosphine)palladium(0) in 2.0 mL of tetrahydrofuran.The resulting mixture was stirred at room temperature for 10 min andthen heated at 50° C. for 1 h. The reaction was quenched by the additionof sat. aqueous NH₄Cl. The mixture was extracted with EtOAc (2×), andwashed with brine. The organic phase was dried over Na₂SO₄ and thenconcentrated in vacuo. The crude material product was purified by flashchromatography (silica, 15% ethyl acetate in hexanes) to afford thetitle compound as a solid.

[0350]¹H NMR (CDCl₃): δ 1.34 (s, 6H), 1.40 (t, J=7.1 Hz, 3H), 2.34 (d,J=4.8 Hz, 2H), 4.37(q,J=7.1 Hz, 2H), 6.22(t, J=4.8 Hz, 1H), 7.02 (d,J=16.4 Hz, 1H), 7.10-7.12 (m, 2H), 7.15 (d, J=16.4 Hz, 1H), 7.29-7.33(m, 1H), 7.37 (d, J=8.0 Hz, 1H), 7.45 (dd, J=1.8, 8.0 Hz, 1H), 7.52 (d,J=8.5 Hz, 2H), 7.53 (d, J=1.8 Hz, 1H), 8.00 (d, J=8.4 Hz, 2H).

[0351](E)-4-[2-(-5,5-Dimethyl-8-(2-thienyl)-5,6-dihydronaphthalen-2-yl)ethenyl]-benzoicAcid (Compound A15)

[0352] Employing the same general procedure as for the preparation of(E)-4-[2-(5,5-dimethyl-5,6,-dihydro-8(7H)-anti-(O-methyloxime)-naphthalen-2-yl)ethenyl]-benzoic acid (Compound A4) 98 mg (0.24mmol) of ethyl(E)-4-[2-(-5,5-dimethyl-8-(2-thienyl)-5,6-dihydronaphthalen-2-yl)ethenyl]-benzoate(Compound A13) was converted into the title compound (white solid).

[0353]¹H NMR (DMSO-D₆): δ 1.27 (s, 6H), 2.32 (d, J=4.8 Hz, 2H), 6.23 t,J=4.8 Hz, 1H), 7.14 (d, J=16.4 Hz, 1H), 7.14-7.15 (overlapping d, 2H),7.36 (d, J=16.4 Hz, 1H), 7.43 (d, J=8.1 Hz, 1H), 7.48 (d, J=1.7 Hz, 1H),7.54 (t, J=3.1 Hz, 1H), 7.62 (dd, J=1.7, 8.1 Hz, 1), 7.68 (d, J=8.4 Hz,2H), 7.88 (d, J=8.4 Hz, 2H).

[0354] Ethyl(E)-4-[2-(5,6-dihydro-5,5-dimethyl-8-(phenylthio)-naphthalenyl)ethenyl]Benzoate (Compound A16)

[0355] To a degassed solution of 0.35 g (1.0 mmol) of2-bromo-5,6-dihydro-5,5-dimethyl-8-(phenylthio)-naphthalene (CompoundA35) and 0.34 g (1.9 mmol) of ethyl 4-vinylbenzoate in 4.0 mL oftriethylamine, was added 0.066 g (0.2 mmol) of tri-o-tolylphosphine andthen 0.025 g (0.1 mmol) of palladium(II) acetate. The reaction washeated at 90° C. for 2.25 h. The reaction was concentrated in vacuo. Theresidue was purified by flash chromatography (silica, 5% ethyl acetatein hexane), followed by recrystallization using EtOH to afford the titlecompound as white crystals.

[0356]¹H NMR (CDCl₃): δ 1.35 (s, 6H), 1.40 (t, J=7.1 Hz, 3H), 2.41 (d,J=4.7 Hz, 2H), 4.38 (q, J=7.1 Hz, 2H), 6.55 (t, J=4.7 Hz, 1H), δ 6.93(d, J=16.3 Hz, 1H), 7.08-7.16 (m, 2H), 7.22-7.27 (m, 6H), 7.32 (d,J=8.2Hz, 1H), 7.38 (dd, J=1.7, 8.0 Hz, 1H), 7.49 (d, J=8.4 Hz, 2H), 7.81 (d,J=1.7 Hz, 1H), 8.00 (d, J=8.4H 2H).

[0357] Ethyl(E)-4-[2-(5,6-dihydro-5,5-dimethyl-8-(phenylsulfonyl)-naphthalenyl)ethenyl]Benzoate (Compound A17)

[0358] To a solution of 0.090 g (0.2 mmol) of ethyl(E)-4-[2-(5,6-dihydro-5,5-dimethyl-8-(phenylthio)-naphthalenyl)ethenyl]benzoate (Compound A16) in 2.0 mL of methylene chloride was addeddropwise a solution of 140 mg (0.45 mmol, 50-60%) ofm-chloroperoxybenzoic acid in 2.0 mL of methylene chloride and thereaction stirred at room temperature for 3.5 h. The mixture was dilutedwith water and extracted with methylene chloride (2×). The organic phasewas dried over MgSO₄ and concentrated in vacuo. The crude product waspurified by flash chromatography (silica, 30% ethyl acetate in hexanes)followed by recrystallization in EtOH to afford the title compound as asolid.

[0359]¹H NMR (CDCl₃): δ 1.22 (s, 6H), 1.42 (t, J=7.1 Hz, 3H), 2.50 (d,J=4.9 Hz, 2H), 4.39 (q, J=7.1 Hz, 2H), 7.00 (d, J=16.4 Hz, 1H), 7.13 (d,J=16.4 Hz, 1H), 7.29 (d, J=8.4 Hz, 1H), 7.40 (dd, J=1.7, 8.1 Hz, 1H),7.46-7.57 (m, 6H), 7.97 (m, 2H), 8.04 (d, J=8.4 Hz, 2H), 8.11 (d, J=1.7Hz, 1H).

[0360](E)-4-[2-(5,6-dihydro-5,5-dimethyl-8-(phenylthio)-naphthalen-2-yl)ethenyl]Benzoic Acid (Compound A18)

[0361] Employing the same general procedure as for the preparation of(E)-4-[2-(5,5-dimethyl-5,6,-dihydro-8(7H)-anti-(O-methyloxime)-naphthalen-2-yl)ethenyl]-benzoic acid (Compound A4), 60 mg (0.14mmol) of ethyl(E)-4-[2-(5,6-dihydro-5,5-dimethyl-8-(phenylthio)-naphthalen-2-yl)ethenyl]benzoate (Compound A16) was converted into the title compound (whitesolid).

[0362]¹H NMR (DMSO-D₆): δ 1.29 (s, 6H), 2.40 (d, J=4.6 Hz, 3H), 6.61 (t,J=4.6 Hz, 1H), 7.05 (d, J=16.4 Hz, 1H), 7.17-7.20 (m, 1H), 7.28-7.35 (m,4H), 7.38 (d, J=8.1 Hz, 1H), 7.52 (dd, J=1.6, 8.1 Hz, 1H), 7.67 (d,J=8.4 Hz, 2H), 7.73 (d, J=1.6 Hz, 1H), 7.90 (d, J=8.4 Hz, 2H).

[0363](E)-4-[-2-(5,6-dihydro-5,5-dimethyl-8-(phenylsulfonyl-naphthalenyl)ethenyl]Benzoic Acid (Compound A19)

[0364] To a cold solution (0° C.) of 61 mg (0.15 mmol) of(E)-4-[2-(5,6-dihydro-5,5-dimethyl-8-(phenylthio)-naphthalen-2-yl)ethenyl]benzoic acid (Compound A18) in 5.0 mL of methylene chloride and 2.0 mLof tetrahydrofuran was added dropwise a cold solution (0° C.) of 70 mg(0.22 mmol, 50-60%) of m-chloroperoxybenzoic acid in 4.0 mL of methylenechloride and the reaction stirred at 0° C. for 7 min. The mixture wasdiluted with water and extracted with methylene chloride (2×). Theorganic phase was dried over Na₂SO₄ and concentrated in vacuo.Recrystallization from acetonitrile gave the title compound as a solid.

[0365]¹H NMR (DMSO-D₆): δ 1.16 (s, 6H), 2.54 (d, J=4.6 Hz, 2H), 7.08 (d,J=16.4 Hz, 1H), 7.35-7.41 (m, 2H), 7.48 (t, J=4.6 Hz, 1H), 7.56 (d,J=8.7 Hz, 1H), 7.63-7.68 (m, 3H), 7.75 (d, J=8.2 Hz, 2H), 7.93-7.96 (m,3H), 8.03 (d, J=8.2 Hz, 2H).

[0366] Ethyl(E)-4-[-2-(5,6-dihydro-5,5-dimethyl-8-(ethylthio)-naphthalen-2-yl)ethenyl]benzoate (Compound A20)

[0367] To a degassed solution of 0.50 g (1.7 mmol) of2-bromo-5,6-dihydro-5,5-dimethyl-8-(ethylthio)-naphthalene (CompoundA36) and 0.45 g (2.5 mmol) of ethyl 4-vinylbenzoate in 4.0 mL oftriethylamine, was added 109 mg (0.36 mmol) of tri-o-tolylphosphine andthen 35 mg (0.16 mmol) of palladium(II) acetate. The reaction was heatedat 90° C. for 2.25 h. The reaction was concentrated in vacuo andpurified by flash chromatography (silica, 2% ethyl acetate in hexane) toafford the title compound as a colorless oil.

[0368]¹H NMR (CDCl₃): δ 1.29 (s, 6H), 1.30 (t, J=7.4 Hz, 3H), 1.41 (t,J=7.1 Hz, 3H), 2.31 (d, J=4.8 Hz, 2H), 2.75 (q, J=7.4 Hz, 2H), 4.38 (q,J=7.1 Hz, 2H), 6.20 (t, J=4.8 Hz, 1H), 7.12 (d, J=16.3 Hz, 1H), 7.24 (d,J=16.3 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.41 (dd, J=1.7, 8.0 Hz, 1H),7.57 (d, J=8.4H, 2H), 7.89 (d, J=1.7 Hz, 1H) 8.02 (d, J=8.4 Hz, 2H).

[0369](E)-4-[-2-(5,6-dihydro-5,5-dimethyl-8-(ethylthio)-naphthalen-2-yl)ethenyl]Benzoic Acid (Compound A21)

[0370] Employing the same general procedure as for the preparation of(E)-4-[2-(5,5-dimethyl-5,6,-dihydro-8(7H)-anti-(O-methyloxime)-naphthalen-2-yl)ethenyl]-benzoic acid (Compound A4), 206 mg (0.52mmol) of ethyl(E)-4-[-2-(5,6-dihydro-5,5-dimethyl-8-(ethylthio)-naphthalen-2-yl)ethenyl]benzoate (Compound A20) was converted into the title compound (whitesolid).

[0371]¹H NMR (DMSO-D₆): δ 1.22 (t, J=7.1 Hz, 3H), 1.23 (s, 6H), 2.27 (d,J=4.9 Hz, 2H), 2.75 (q, J=7.1 Hz, 2H), 6.15 (t, J=4.9 Hz, 1H), 7.24 (d,J=16.4 Hz, 1H), 7.37 (d, J=8.1 Hz, 1H), 7.45 (d, J=16.4 Hz, 1H), 7.75(m, 3H), 7.92 (d, J=8.1 Hz, 2H).

[0372](E)-4-[-2-(5,6-dihydro-5,5-dimethyl-8-(ethylsulfonyl)-naphthalen-2-yl)ethenyl]Benzoate (Compound A22)

[0373] To a cold solution (0° C.) of 44 mg (0.12 mmol) of ethyl(E)-4-[2-(5,6-dihydro-5,5-dimethyl-8-(ethylthio)-naphthalen-2-yl)ethenyl]benzoic acid (Compound A21) in 4.0 mL of methylene chloride and 0.5 mLof tetrahydrofuran was added dropwise a cold solution (0° C.) of 55 mg(0.18 mmol, 50-60%) of m-chloroperoxybenzoic acid in 3.0 mL of methylenechloride and the reaction stirred at 0° C. for 30 min. The mixture wasdiluted with water and extracted with methylene chloride (2×). Theorganic phase was diluted with EtOAc, dried over Na₂SO₄ and thenconcentrated in vacuo. Recrystallization from acetonitrile gave thetitle compound as a solid.

[0374]¹H NMR (DMSO-D₆): δ 1.16 (t, J=7.3 Hz, 1H), 1.25 (s, 6H), 2.50 (d,J=4.8 Hz, 2H), 3.32 (q, J=7.3 Hz, 2H), 7.18 (t, J=4.8 Hz, 1H), 7.25 (d,J=16.4 Hz, 1H), 7.46 (d, J=16.4 Hz, 1H), 7.49 (d, J=8.1 Hz, 1H), 7.71(dd, J=1.5, 8.1 Hz, 1H), 7.76 (d, J=8.4 Hz, 2H), 7.94 (d, J=8.4 Hz, 2H),8.04 (d, J=1.5 Hz, 1H).

[0375] Ethyl(E)-4-[-2-(5,6,7,8-tetrahydro-5,5-dimethyl-8-(1,3-dithian-2-yl)naphthalen-2-yl)ethenyl]Benzoate (Compound A23)

[0376] To a cold solution (0° C.) of 140 mg (0.40 mmol) of ethyl(E)-4-[2-(5,5-dimethyl-5,6,-dihydro-naphthalen-8(7H)-one-2-yl)ethenyl]-benzoate(Compound A2), in 6.0 mL of methylene chloride was added dropwise 130 mg(0.12 mL, 1.2 mmol) of 1,3-propanedithiol and 0.17 g (0.15 mL, 102 mmol)of borontrifluoride diethyl etherate. The reaction stirred between 0° C.and room temperature for 4 h. The mixture was diluted with aqueous sat.potassium carbonate, and extracted with ether (2×). The organic phasewas washed with brine, dried over MgSO₄ and then concentrated in vacuo.The crude product was purified by flash chromatography (silica, 10%ethyl acetate in hexane) to afford the title compound as a solid.

[0377]¹H NMR (CDCl₃): δ 1.29 (s, 6H), 1.39 (t, J=7.1 HE, 3H), 1.83 (m,2H), 2.00 (m, 1H), 2.09 (m, 1H), 2.62 (m, 2H), 2.74 (m, 2H), 3.17 (m,2H), 4.36 (q, J=7.1 Hz, 2H); 7.09 (d, J=16.4 Hz, 1H), 7.20 (d, J=16.4Hz, 1H), 7.30 (d, J=8.2 Hz, 1H), 7.41 (dd, J=1.9, 8.2 Hz, 1H), 7.55 (d,J=8.4 Hz, 2H), 8.00 (d, J=8.4 Hz, 1H), 8.10 (d, J=1.9 Hz, 2H).

[0378](E)-4-[2-(5,6,7,8-Tetrahydro-5,5-dimethyl-8-(2-(1,3-dithian-2-yl)naphthalenyl)ethenyl]-benzoicAcid (Compound A24)

[0379] Employing the same general procedure as for the preparation of(E)-4-[2-(5,5-dimethyl-5,6,-dihydro-8(7H)-anti-(O-methyloxime)-naphthalen-2-yl)ethenyl]-benzoic acid (Compound A4), 81 mg (0.18mmol) of ethyl(E)-4-[2-(5,6,7,8-tetrahydro-5,5-dimethyl-8-(1,3-dithian-2-yl)naphthalen-2-yl)ethenyl]benzoate (Compound A23) was converted into the title compound (whitesolid).

[0380]¹H NMR (CD₃OD): δ 1.28 (s, 6H), 1.83 (m, 2H), 1.93 (m, 1H), 2.19(m, 1H), 2.66 (m, 4H), 3.22 (m, 2H), 7.18 (d, J=16.4 Hz, 1H), 7.28 (d,J=16.4 Hz, 1H), 7.36 (d, J=8.2 Hz, 1H), 7.48 (dd, J=1.9, 8.2 Hz, 1H),7.66 (d, J=8.4 Hz, 2H, 8.00 (d, J=8.4 Hz, 1H), 8.12 (d, J=1.9 Hz, 2H).

[0381] Ethyl(E)-4-[2-(5,6-tetrahydro-5,5-dimethyl-8-(propyliden-2-yl)-naphthalen-2-yl)ethenyl]-benzoate(Compound A25)

[0382] To a degassed solution of 0.36 g (1.3 mmol) of7-bromo-1(2H)-(propyliden-2-yl)-3,4-dihydro-4,4-dimethylnaphthalene(Compound A37) and 0.44 g (2.5 mmol) of ethyl 4-vinylbenzoate in 3.6 g(5.0 mL, 36 mmol) of triethylamine, was added 88 mg (0.29 mmol) oftri-o-tolylphosphine and then 33 mg (0.15 mmol) of palladium(II)acetate. The reaction was heated at 95° C. for 4 h. The reaction wasconcentrated in vacuo and purified by flash chromatography (silica, 1%ethyl acetate in hexane) to afford the title compound as an oil.

[0383]¹H NMR (CDCl₃): δ 1.24 (s, 6H), 1.39 (t, J=7.1 Hz, 3H), 1.64 (t,J=6.8 Hz, 2H), 1.89 (s, 3H), 2.00 (s, 3H), 2.51 (t, J=6.8 Hz, 2H), 4.38(q, J=7.1 Hz, 2H), 7.02 (d, J=16.4 Hz, 1H), 7.18-7.37 (overlapping d,3H), 7.41 (s, 1H), 7.58 (d, J=8.4 Hz, 2H), 8.02 (d, J=8.4 Hz, 2H).

[0384](E)-4-[2-(5,6-dihydro-5,5-dimethyl-8(7H)-(propyliden-2-yl)-naphthalen-2-yl)ethenyl]-benzoicAcid (Compound A26)

[0385] Employing the same general procedure as for the preparation of(E)-4-[2-(5,5-dimethyl-5,6,-dihydro-8(7H)-anti-(O-methyloxime)-naphthalen-2-yl)ethenyl]benzoic acid (Compound A4) 95 mg (0.25mmol) of ethyl(E)-4-[2-(5,6,7,8-tetrahydro-5,5-dimethyl-8-(methylethyliden-2-yl)naphthalen-2-yl)ethenyl]benzoate(Compound A25) was converted into the title compound using 1.0 mL (2.3mmol) of LiOH (2.3 M aqueous solution).

[0386]¹H NMR (CDCl₃): δ 1.26 (s, 6H), 1.64 (t, J=6.9 Hz, 2H), 1.86 (s,3H), 2.02 (s, 3H), 2.53 (t, J=6.9 Hz, 2H), 7.07 (d, J=16.4 Hz, 1H),7.22-7.38 (overlapping d, 3H), 7.42 (s, 1H), 7.58 (d, J=8.4 Hz, 2H),8.08 (d, J=8.4 Hz, 2H).

[0387] Ethyl(E)-4-[2-(7,8-dihydro-5,5-dimethyl-8(7H)-(pentyliden-3-yl)-naphthalen-2-yl)ethenyl]-benzoate(Compound A27)

[0388] To a degassed solution of 0.30 g (0.98 mmol) of7-bromo-1(2H)-(pentyliden-3-yl)3,4-dihydro-4,4-dimethylnaphthalene(Compound A38) and 0.17 g (0.97 mmol) of ethyl 4-vinylbenzoate in 3.63 g(5.0 mL, 36 mmol) of triethylamine, was added 61 mg (0.2 mmol) oftri-o-tolylphosphine and then 23 mg (0.10 mmol) of palladium(II)acetate. The reaction was heated at 95° C. for 6.5 h. The reaction wasthen concentrated in vacuo and purified by flash chromatography (silica,100% hexane) followed by recrystallization from ethanol gave the titlecompound as white crystals.

[0389]¹H NMR (CDCl₃): δ 1.05 (t, J=7.3 Hz, 3H), 1.20 (t, J=7.4 Hz, 3H),1.24 (s, 6H), 1.39 (t, J=7.2 Hz, 3H), 1.65 (t, J=6.8 Hz, 2H), 2.22 (q,J=7.4 Hz, 2H), 2.31 (q, J=7.3 Hz, 2H), 2.50 (t, J=6.8 Hz, 2H), 4.36 (q,J=7.2 Hz, 2H), 7.04 (d, J=16.4 Hz, 1H), 7.17 (d, J=16.4 Hz, 11H), 7.28(d, J=8.1 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 7.39 (s, 1H), 7.53 (d, J=8.4Hz, 2H), 8.00 (d, J=8.4 Hz, 2H).

[0390](E)-4-[2-(5,6-Dihydro-5,5-dimethyl-8(7H)-(pentyliden-3-yl)-naphthalen-2-yl)ethenyl]benzoicAcid (Compound A28)

[0391] Employing the same general procedure as for the preparation of(E)-4-[2-(5,5-dimethyl-5,6,-dihydro-8(7H)-anti-(O-methyloxime)-naphthalen-2-yl)ethenyl]-benzoic acid (Compound A4), 150 mg (0.37mmol) of ethyl(E)-4-[2-(5,6,-dihydro-5,5-dimethyl-8(7H)-(pentyliden-3-yl)-naphthalen-2-yl)ethenyl]-benzoate(Compound A27) was converted into the title compound (white solid).

[0392]¹H NMR (Acetone-D₆): δ 1.08 (t, J=7.4 Hz, 3H), 1.22 (t, J=7.1 Hz,3H), 1.26 (s, 6H), 1.67 (t, J=7.1 Hz, 3H), 2.25 (q, J=7.4 Hz, 2H), 2.33(q, J=7.4 Hz, 2H), 2.50 (t, J=7.1 Hz, 2H), 7.13 (d, J=16.4 Hz, 1H), 7.28(d, J=16.4 Hz, 1H), 7.31 (d, J=8.6 Hz, 1H), 7.34 (m, 2H), 7.62 (d, J=8.4Hz, 2H), 7.98 (d, J=8.4 Hz, 2H).

[0393] Ethyl(E)-4-[2-(5,6-dihydro-5,5-dimethyl-8(2n-(cyclohexylidenyl)naphthalen-2-yl)ethenyl]-benzoate(Compound A29)

[0394] To a degassed solution of 0.40 g (1.3 mmol) of7-bromo-1(2H)-(cyclohexylidenyl)-3,4-dihydro-4,4-dimethylnaphthalene(Compound A39) and 0.62 g (3.5 mmol) of ethyl 4-vinylbenzoate in 2.2 g(3.0 mL, 22 mmol) of triethylamine, was added 76 mg (0.25 mmol) oftri-o-tolylphosphine and then 29 mg (0.13 mmol) of palladium(II)acetate.

[0395] The reaction was heated at 95° C. for 2.5 h. The reaction wasthen concentrated in vacuo and purified by flash chromatography (silica,1% ethyl acetate in hexane) to afford the title compound as a whitesolid.

[0396]¹H NMR (CDCl₃): δ 1.27 (s, 6H), 1.39 (t, J=7.1 DH, 3H), 1.62 (m,8H), 2.34 (m, 2H), 2.53 (m, 4H), 4.37 (q, J=7.1 Hz, 2H), 7.04 (d, J=16.4Hz, 1H), 7.18 (d, J=16.4 Hz, 1H), 7.28-7.35 (m, 3H), 7.53 (d, J=8.4 Hz,2H), 8.01 (d, J=8.4 Hz, 2H).

[0397](E)-4-[2-(5,6-Dihydro-5,5-dimethyl-8(7H)-(cycloheylidenyl)-naphthalen-2-yl)ethenyl]benzoicAcid (Compound A31)

[0398] Employing the same general procedure as for the preparation of(E)₄-[2-(5,5-dimethyl-5,6,-dihydro-8(7H)-anti-(O-methyloxime)-naphthalen-2-yl)ethenyl]-benzoic acid (Compound A4), 280 mg (0.68mmol) of ethyl(E)-4-[2-(5,6-dihydro-5,5-dimethyl-8(7H)-(cyclohexylidenyl)-naphthalen-2-yl)ethenyl]benzoate(Compound A29) was converted into the title compound using 2.0 mL (3.3mmol) of LiOH (1.7 M aqueous solution).

[0399]¹H NMR (DMSO-D₆): δ 1.28 (s, 6H), 1.59-1.67 (m, 8H), 2.36 (m, 2H),2.48-2.57 (m, 4H), 7.08 (d, J=16.3 Hz, 1H), 7.20-7.38 (m, 5H), 7.59 (d,J=8.4 Hz, 1H), 8.09 (d, J=8.4 Hz, 2H).

[0400] (+/−) Ethyl(E)-4-[2-(5,6,7,8-tetrahydro-5,5-dimethyl-8-hydroxy-8-(methylcarbethoxy)-naphthalen-2-yl)ethenyl]benzoate(Compound A32)

[0401] To a refluxing solution of 0.75 g (11.5 mmol) of granular zinc in5.0 mL of benzene was added a solution of ethyl(E)-4-[2-(5,5-dimethyl-5,6,-dihydro-naphthalen-8(7H)-one-2-yl)ethenyl]-benzoate(Compound A2) in 5.0 mL of benzene followed by 0.27 g (0.18 mmol) ofethyl bromoacetate. The resulting mixture was refluxed for 24 h. Thereaction was cooled, filtered through celite. The filtrate was washedwith 10% HCl, sat. aqueous NaHCO₃ and brine. The organic phase was driedover Na₂SO₄ and concentrated in vacuo. The crude material was purifiedby flash chromatography (silica, 10% ethyl acetate in hexane) to affordthe title compound as a white solid.

[0402]¹H NMR (CDCl₃): δ 1.30 (t, J=7.1 Hz, 3H), 1.30 (3H, s), 1.34 (3H,s), 1.41 (t, J=7.1 Hz, 3H), 1.77 (m, 2H), 2.09 (m, 2H), 2.82 (d, J=3.4Hz, 2H), 4.17 (s, 1H), 4.22 (q, J=7.1 Hz, 2H), 4.38 (q, J=7.1 Hz, 2H),7.10 (d, J=16.4 Hz, 1H), 7.20 (d, J=16.4 Hz, 1H), 7.31 (d, J=8.2 Hz,1H), 7.42 (dd, J=1.9, 8.2 Hz, 1H), 7.55 (d, J=8.4 Hz, 2H), 7.75 (d,J=1.9 Hz, 1H), 8.03 (d, J=8.4 Hz, 2H).

[0403] Ethyl(E)-4-[2-(5,6-dihydro-5,5-dimethyl-8-(methylcarbethoxy)naphthalen-2-yl)ethenyl]benzoate(Compound A33a)

[0404] Ethyl (E)-4-[2-(5,6-dihydro-5,5-dimethyl-8(2H)-anti(carbethoxymethylidenyl)-naphthalen-2-yl)ethenyl]benzoate (CompoundA33b)

[0405] To a solution of 0.25 g (0.57 mmol) of (+/−)ethyl(E)-4-[2-(5,6,7,8-tetrahydro-5,5-dimethyl-8-hydroxy-8-(methylcarbethoxy)-naphthalen-2-yl)ethenyl]benzoate (Compound A32) in 11.0 mL of benzene was added 1.0 g (4.2 mmol)of Burgess reagent and the resulting solution was heated at 55° C. for30 min. The reaction was cooled and concentrated in vacuo, the residuewas diluted with water and extracted with EtOAc (2×), the organic layerswere washed with brine, dried over Na₂SO₄, and concentrated in vacuo toafford a mixture of title compounds in a 3:1 ratio (endo: exo). Thetitle compounds were seperated by flash chromatography (silica, 5% ethylacetate in hexane) to afford the pure isomers as white solids.

[0406] Compound A33a:

[0407]¹H NMR (CDCl₃) δ 1.21 (t, J=7.1 Hz, 3H, 1.30 (s, 6H), 1.41 (t,J=7.1 Hz, 3H), 2.82 (d, J=4.3 Hz, 2H), 3.51 (s, 2H), 4.12 (q, J=7.1 Hz,2H), 4.38 (q, J=7.1 Hz, 2H), 5.97 (t, J=4.3 Hz, 1H), 7.05 (d, J=16.4 Hz,1H), 7.19 (d, J=16.4 Hz, 1H), 7.30-7.40 (m, 3H), 7.47 (d, J=8.4 Hz, 2H),8.03 (d, J=8.4 Hz, 2H).

[0408] 4,4-Dimethyl-7-bromo-1-phenylthio-3,4-dihydronaphthalene(Compound A35)

[0409] To a stirred solution of4,4-dimethyl-7-bromo-3,4-dihydronaphthalen-1(2H)one (Compound G, 1.48 g,5.9 mmol), titanium tetrachloride (1.09 g, 5.7 mmol) and THF (10 mL) wasadded a mixture of thiophenol (660 mg, 6 mmol), triethylamine (1.16 g,11.5 mmol) and THF (20 mL) via an addition funnel at ambienttemperature. The mixture was stirred for 5 h, and water (10 mL) wasadded, extracted with ether (3×50 mL). The combined organic layer waswashed successively with water (10 mL), 10% NaHCO₃ (10 mL) and brine (10mL). The organic layer was dried (MgSO₄) and the solvent distilled offat reduced pressure. After silicagel chromatography the title compoundwas obtained as a colorless oil

[0410]¹H NMR (CDCl₃): δ 1.31 (s, 6H, 2.39 (d, J=4.9 Hz, 2H, 6.54 (t,J=4.9 Hz, 1H), 7.10-7.35 (m, 7H, 7.78 (d, J=2.0 Hz, 1H).

[0411] 2-Bromo-5,6-dihydro-5,5-dimethyl-8-(ethylthio)-naphthalene

[0412] (Compound A36)

[0413] To a solution of 1.03 g (4.1 mmol) of7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound G) in30.0 mL of tetrahydrofuran, was added dropwise 0.49 g (0.85 mL, 7.8mmol) of titaniumtetrachloride and the resulting solution stirred for 10min. A solution of 35 mg (0.50 mL, 6.7 mmol) of ethanethiol and 0.54 g(0.75 mL, 5.4 mmol) of triethylamine in 10.0 mL of tetrahydrofuran wasadded and the reaction stirred at room temperature for 13 h. The mixturewas diluted with water and extracted with ether (2×). The organic phasewas washed with brine, dried over Na₂SO₄ and then concentrated in vacuo.Purification by flash chromatography (silica, 100% hexane) gave thetitle compound as an oil.

[0414]¹H NMR (CDCl₃): δ 1.25 (s, 6H), 1.27 (t, J=7.1 Hz, 3H), 2.29 (d,J=4.8 Hz, 2H), 2.70 (q, J=7.1 Hz, 2H), 6.23 (t, J=4.8 Hz, 1H), 7.17 (d,J=8.2 Hz, 1H), 7.35 (dd, J=1.7, 8.2 Hz, 1H), 7.85 (d, J=62.1 Hz, 2H).

[0415]7-Bromo-1(2H)-(propyliden-2-yl)-3,4-dihydro-4,4-dimethylnaphthalene(Compound A37)

[0416] To a slurry of titanium trichloride (5 g, 32 mmol) in DME (80 mL)was added lithium wire in small portions (0.7 g, 100 mmol) under argonatmosphere. The mixture was refluxed for 1 h, cooled to ambienttemperature and a solution of acetone (928 mg, 16 mmol) and7-bromo-3.4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound G, 1.0 g,3.96 mmol) in 20 mL of DME was added. The resultant mixture was refluxedfor 16 h under argon atmosphere. The reaction mixture was then cooled toambient temperature and diluted with hexane (100 mL), And thereafterfiltered through a pad of florisil. The filtrate was concentrated underreduced pressure and purified by flash chromatography (silica, 100%hexane) to afford the title compound as a colorless oil.

[0417]¹H NMR (CDCl₃): δ 1.19 (s, 6H), 1.56 (t, J=6.9 Hz, 2H), 1.81 (s,3H), 1.94 (s, 3H), 2.44 (t, J=7.1 Hz, 2H), 7.11 (d, J=8.3 Hz, 1H), 7.23(dd, J=2.1, 8.4 Hz, 1H), 7.35 (d, J=2.1 Hz, 1H).

[0418]7-Bromo-1(2H)-(pentyliden-2-yl)-3,4-dihydro-4,4-dimethylnaphthalene(Compound A38)

[0419] Employing the same general procedure as for the preparation of7-bromo-1 (2H)-(propyliden-2-yl)-3,4-dihydro-4,4-dimethylnaphthalene(Compound A37), 1.0 g (3.97 mmol) of4,4-dimethyl-7-bromo-3,4-dihydronaphthalen-1 (2H)one (Compound G) wasconverted into the title compound using 1.37 g (15.9 mmol) of3-pentanone, 1.92 g (277 mmol) of lithium and 12.2 g (79.4 mmol) oftitanium trichloride.

[0420]¹H NMR (CDCl₃): δ 1.04 (t, J=7.5 Hz, 3H), 1.14 (t, J=7.5 Hz, 3H),1.23 (s, 6H), 1.63 (t, J=7.1 Hz, 2H), 2.21 (q, J=7.5 Hz, 2H), 2.29 (q,J=7.5 Hz, 2H), 2.49 (t, J=7.1 Hz, 2H), 7.15 (d, J=8.3 Hz, 1H), 7.29 (dd,J=2.2, 8.3 Hz, 1H), 7.36 (d, J=2.2 Hz, 1H).

[0421]7-Bromo-1(2H)-(cyclohexylidenyl)-3,4-dihydro-4,4-dimethylnaphthalene(Compound A39)

[0422] Employing the same general procedure as for the preparation of7-bromo-1(2H)-(propyliden-2-yl)-3,4-dihydro-4,4-dimethylnaphthalene(Compound A37), 1.0 g (3.97 mmol) of4,4-dimethyl-7-bromo-3,4-dihydronaphthalen-1(2H)one (Compound G) wasconverted into the title compound using 1.56 g (15.9 mmol) ofcyclohexanone, 1.92 g (277 mmol) of lithium and 12.2 g (79.4 mmol) oftitanium trichloride.

[0423]¹HMR (CDCl₃): δ 1.23 (s, 6H), 1.50-1.65 (m, 8H), 2.33 (br s, 2H),2.45 (t, J=5.5 Hz, 2H), 2.50 (t, J=7.1 Hz, 2H), 7.15 (d, J=8.1 Hz, 1H),7.26 (d, J=1.6 Hz, 1H), 7.29 (br s, 1H).

[0424]Ethyl-6-[5,6,7,8-tetrahydro-5,5-dimethyl-naphth-7-yl]naphth-2-oate(Compound B1)

[0425] To a degassed solution of 0.39 g (1.4 mmol) of ethyl6-bromo-naphthalene-2-carboxylate and 3.0 mL of toluene, was addedsequentially 49 mg (0.04 mmol) of tetrakis-triphenylphosplinepalladium(0), 2.0 mL (2.0 mmol) of 1M sodium carbonate and then asolution of 0.32 g (1.6 mmol) of(5,6,7,8-tetrahydro-5,5-dimethylnaphth-2-yl)boronic acid (Compound B13)in 3.0 mL of MeOH. The reaction was heated at 80° C. for 6 h, dilutedwith 2N Na₂CO₃, and extracted with CH₂C₂ (2×), the organic layer waswashed with brine, dried over MgSO₄, and concentrated in vacuo to givean oil. Flash chromatography (silica, 5% ethyl acetate in hexane) of thecrude material gave the title compound as a white solid.

[0426]¹H NW (CDCl₃, 300 MHz): δ 1.35 (s, 6H), 1.46 (t, J=7.1 Hz, 3H),1.70-1.74 (m, 2H), 1.85-1.89 (m, 2H), 2.88 (t, J=6.3 Hz, 2H), 4.46 (q,J=7.1 Hz, 2H), 7.42 (d, J=1.7 Hz, 1H), 7.46 (d, J=8.2 Hz, 1H), 7.52 (dd,J=2.0, 8.2 Hz, 1H), 7.80 (dd, J=1.7, 8.5 Hz, 1H), 7.91 (d, J=8.6 Hz,1H), 8.00 (d, J=8.5 Hz, 1H), 8.05 (s, 1H), 8.08 (dd, J=1.7, 8.6 Hz, 1H),8.61 (s, 1H).

[0427] 6-[5,6,7,8-Tetrahydro-5,5-dimethyl-naphth-7-yl]-2-naphthoic Acid(Compound B2)

[0428] Employing the same general procedure as for the preparation ofE)-4-[2-(5,6,7,8-tetrahydro-5,5-dimethyl-8-anti-(O-methyloxime)-naphthalen-2-yl)ethenyl]-benzoic acid (Compound A4) 50 mg (0.14mmol) ofethyl-6-[5,6,7,8-tetrahydro-5,5-dimethyl-naphth-7-yl]naphth-2-oate(Compound B1) was converted into the title compound (white solid).

[0429]¹H NMR (DMSO-D6, 300 MHz): δ_(—)1.28 (s, 6H), 1.64-1.68 (m, 2H,1.77-1.80 (m, 2H), 2.82 (t, J=5.7 Hz, 2H), 7.48 (d, J=8.4 Hz, 1H), 7.49(s, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.89 (dd J=1.8, 8.7 Hz, 1H), 7.98 (dd,J=1.8, 8.7 Hz, 1H), 8.05 (d, J=8.7 Hz, 1H), 8.17 (d, J=8.7 Hz, 1H), 8.24(s, 1H), 8.60 (s, 1H).

[0430]Ethyl-6-[5,6,7,8-tetrahydro-5,5-dimethyl-8-(t-butyldimethylsilyloxy)-naphth-7-yl]naphth-2-oate(Compound B3)

[0431] To a degassed solution of 722 mg (2.6 mmol) of ethyl6-bromo-naphthalenecarboxylate in 6.0 mL of toluene, was addedsequentially 90 mg (0.08 mmol) of tetrakis-triphenylphosphine palladium(0), 5.0 mL (10.0 mmol) of 2M sodium carbonate, and a solution of 1.018g (3.1 mmol) of(5,6,7,8-tetrahydro-5,5-dimethyl-8-(t-butyldimethylsilyloxy)naphth-2-yl)boronicacid (Compound B14) in 3.0 mL of MeOH. The reaction was heated at 90° C.for 15 h. The reaction was diluted with 2N Na₂CO3, and extracted withCH₂Cl₂ (2×), the organic layer was washed with brine, dried over MgSO₄,and concentrated in vacuo to give an oil. The crude product was purifiedflash chromatography (silica, 5% ethyl acetate in hexane) to afford thetitle compound as a white solid.

[0432]¹H NMR (CDCl₃, 300): δ_(—)0.20 (s, 3H), 0.23 (s, 3H), 1.00 (s,9H), 1.35 (s, 6H), 1.46 (t, 3H, J=7.1 Hz), 1.70-2.10 (m, 4H), 4.46 (q,J=7.1 Hz, 2H), 4.83 (dd, J=4.7, 8.2 Hz, 1H), 7.42 (d, J=8.2 Hz, 1H),7.60 (dd, J=2.1, 8.2 Hz, 1H), 7.79-7.82 (overlapping s, dd, 2H), 7.90(d, J=8.7 Hz, 1H), 7.92 (d, J=8.5 Hz, 1H), 8.06-8.1 (overlapping s, dd,2H), 8.62 (s, 1H).

[0433]Ethyl-6-[5,6,7,8-tetrahydro-5,5-dimethyl-8-hydroxy-naphth-7-yl]naphth-2-oate(Compound B4)

[0434] To a cold (0° C.) solution of 1.15 g (2.4 mmol) ofethyl-6-[5,6,7,8-tetrahydro-5,5-dimethyl-8-(t-butyldimethylsilyloxy)-naphth-7-yl]naphth-2-oate

[0435] (Compound B3) in 12.0 mL of tetrahydrofuran, was added 3.1 g(12.0 mL, 12.0 mmol, 1.0 M in tetrahydrofuran) oftetrabutylammoniumfluoride and the mixture was stirred between 0° C. toroom temperature for 3 h. The reaction was then concentrated in vacuo,diluted with water, and extracted with ether (2×), the organic layer waswashed with brine, dried over MgSO₄, and concentrated in vacuo to give asolid. Recrystallization from ethanol gave the title compound as a whitesolid.

[0436]¹H NMR (CDCl₃, 300 MHz): δ_(—)1.32 (s, 3H), 1.39 (s, 3H), 1.46 (t,J=7.1 Hz, 3H), 1.66-1.72 (m, 1H), 1.90-1.99 (m, 3H), 2.11-2.20 (m, 1H),4.47 (q, J=7.1 Hz, 2H), 4.85 (t, J=5.0 Hz, 1H), 7.46 (d, J=8.2 Hz, 1H),7.63 (dd, J=2.1, 8.2 Hz, 1H), 7.81 (dd, J=1.8, 8.7 Hz, 1H), 7.83 (s,1H), 7.90 (d, J=8.5 Hz, 1H), 8.00 (d, J=8.7 Hz, 1H), 8.08 (overlapping,2H), 8.61 (s, 1H.

[0437]6-[5,6,7,8-Tetrahydro-5,5-dimethyl-8-hydroxy-naphth-7-yl]-2-naphthoicAcid

[0438] (Compound B5)

[0439] Employing the same general procedure as for the preparation of(E)-4-[2-(5,6,7,8-tetrahydro-5,5-dimethyl-8-anti-(O-methyloxime)-naphthalen-2-yl)ethenyl]-benzoic acid (Compound A4) 124 mg (0.33mmol) ofethyl-6-[5,6,7,8-tetrahydro-5,5-dimethyl-8-hydroxy-naphth-7-yl]naphth-2-oate(Compound B4) was converted into the title compound.

[0440]¹H NMR (DMSO, 300 MHz): δ_(—)1.25 (s, 3H), 1.29 (s, 3H), 1.58-1.99(m, 4H), 3.33 (s, 1H), 4.62 (s, 1H), 7.47 (d, J=8.2 Hz, 1H), 7.66 (dd,J=2.0, 8.2 Hz, 1H), 7.85 (d, J=2.0 Hz, 1H), 7.89 (dd J=1.7, 8.6 Hz, 1H),8.00 (dd, J=1.7, 8.6 Hz, 1H), 8.07 (d, J=8.6 Hz, 1H), 8.19 (d, J=8.6 Hz,1H), 8.24 (s, 1H), 8.61 (s, 1H).

[0441]Ethyl-6-[5,5-dimethyl-5,6-dihydro—naphthlen-8(7H)-one-2-yl]-naphthalen-2-oate(Compound B6)

[0442] To a solution of 101 mg (0.27 mmol) ofethyl-6-[5,6,7,8-tetrahydro-5,5-dimethyl-8-hydroxy-naphth-7-yl]naphth-2oate(Compound B4) in 1.5 mL of methylene chloride was added 50 mg (0.43mmol) of N-methylmorpholine N-oxide and 6.0 mg (0.017 mmol) oftetrapropylammonium perruthenate(VII). The reaction was stirred at roomtemperature for 3 h, diluted with water, and extracted with CH₂Cl₂ (2×).The combined organic layer was washed with brine, dried over MgSO₄, andconcentrated in vacuo to give a foam. The title compound was obtained asa white solid after flash chromatography (silica, 10% ethyl acetate inhexane).

[0443]¹H NMR (CDCl₃, 300 MHz): δ 1.46 (overlapping s, 6H), 1.46(overlapping t, J=7.1 Hz, 3H), 2.09 (t, J=6.4 Hz, 2H), 2.80 (t, J=6.4Hz, 2H), 4.46 (q, J=7.1 Hz, 2H), 7.57 (d, J=8.2 Hz, 1H), 7.83 (dd,J=1.8, 8.6 Hz, 1H), 7.90-7.95 (several d, 2H), 8.04 (d, J=8.4 Hz, 1H),8.09-8.12 (overlapping s, dd, 2H), 8.41 (d, J=2.1 Hz, 1H), 8.63 (s, 1H).

[0444] 6-[5,5-Dimethyl-5,6-dihydro—naphthlen-8(7H)-one-2-yl]-2-naphthoicacid (Compound B7)

[0445] Employing the same general procedure as for the preparation of(E)-4-[2-(5,6,7,8-tetrahydro-5,5-dimethyl-8-anti-(O-methyloxime)-2-naphthalenyl)ethenyl]-benzoic acid (Compound A4) 58 mg (0.16mmol) of ethyl-6-[5,5-dimethyl-5,6-dihydro—naphthlen-8(7H)-one-2-yl]-naphthalen-2-oate(Compound B6) was converted into the title compound (white solid).

[0446]¹H NMR (DMSO-D6, 300 MHz): δ_(—)1.41 (s, 6H), 2.01 (t, J=6.7 Hz,2H), 2.74 (t,J=6.7 Hz, 2H), 7.71 (d,J=8.3 Hz, 1H), 7.93 (dd, J=1.8, 8.7Hz, 1H), 7.93 (dd, J=1.7, 8.5 Hz, 1H), 8.07-8.13 (several d, 3H), 8.22(d, J=8.5 Hz, 1H), 8.26 (s, 2H), 8.32 (s, 1H), 8.63 (s, 1H).

[0447]Ethyl-6-[5,6,7,8-tetrahydro-5,5-dimethyl-8-(methoethyloxy)-naphth-7-yl]naphth-2-oate(Compound B5)

[0448] To a cold (0° C.) solution of 130 mg (0.35 mmol) ofethyl-6-[5,6,7,8-tetrahydro-5,5-dimethyl-8(hydroxy)-naphth-7-yl]naphth-2-oate(Compound B4) in 2.0 mL of methylene chloride was added 50 mg (0.15 mL,0.86 mmol) of Hunig's base, followed by 0.21 g (0.20 mL, 2.6 mmol)chloromethyl methyl ether was added and stirred at room temperature for14 h. About 500 mgs of t-butylammonium iodide was then added and thereaction was warmed to 35° C. for one additional hour. The reaction wasdiluted with water, and extracted with CH₂Cl₂ (2×). The combined organiclayer was washed with brine, dried over MgSO₄, and concentrated in vacuoto give an oil. The title compound was obtained as an oil after flashchromatography (silica, 10% ethyl acetate).

[0449]¹H NMR (CDCl₃, 300 MHz): δ 1.31 (s, 3H), 1.40 (s, 3H), 1.46 (t,3H, J=7.1 Hz), 1.60 (m, 1H), 1.98-2.08 (m, 3H), 3.51 (s, 3H), 4.46 (q,J=7.1 Hz, 2H), 4.75 (t, J=4.5 Hz, 1H), 4.83 (d, J=7.0 Hz, 1H), 4.93 (d,J=7.0 Hz, 1H), 7.48 (d, J=8.2 Hz, 1H), 7.63 (dd, J=2.0, 8.2 Hz, 1H),7.70 (d, J=2.0 Hz, 1H), 7.80 (dd J=1.7, 8.5 Hz, 1H), 7.92 (d, J=8.5 Hz,1H), 8.01 (d, J=8.7 Hz, 1H), 8.05 (s, 1H), 8.09 (dd, J=1.7, 8.7 Hz, 1H),8.62 (s, 1H).

[0450]6-[5,6,7,8-Tetrahydro-5,5-dimethyl-8-(methoxymethyloxy)-naphth-7-yl]-2-naphthoicAcid (Compound B9)

[0451] Employing the same general procedure as for the preparation of(E)-4-[2-(5,6,7,8-tetrahydro-5,5-dimethyl-8-anti-(O-methyloxime)-2-naphthalenyl)ethenyl]-benzoic acid (Compound A4) 90 mg (0.21mmol) ofethyl-6-[5,6,7,8-tetrahydro-5,5-dimethyl-8-(methoxymethyloxy)-naphth-7-yl]naphth-2-oate(Compound B8) was converted into the title compound (white solid).

[0452]¹H NMR (DMSO-D6, 300 MHz): δ_(—)1.26 (s, 3H), 1.34 (s, 3H), 1.59(m, 1H), 1.98 (m, 3H), 3.34 (s, 3H), 4.68 (t, J=4.5 Hz, 1H), 4.78 (d,J=6.8 Hz, 1H), 4.84 (d, J=6.8 Hz, 1H), 7.54 (d, J=8.3 Hz, 1H), 7.70 (s,1H), 7.73 (d, J=8.3 Hz, 1H), 7.90 (d J=8.7 Hz, 1H), 8.00 (d, J=8.7 Hz,1H), 8.09 (d, J=8.7H, 1H), 8.21 (d, J=8.7 Hz, 1H), 8.24(s, 1H), 8.63 (s,1H).

[0453]Ethyl-6-[5,6,7,8-tetrahydro-5,5-dimethyl-8-(O-acetyl)-naphth-7-yl]naphth-2-oate

[0454] (Compound B10)

[0455] To a cold (0° C.) solution of 61 mg (0.16 mmol) ofethyl-6-[5,6,7,8-tetrahydro-5,5-dimethyl-8-hydroxy)-naphth-7-yl]naphth-2-oate(Compound B4) in 2.0 mL of methylene chloride stirring under argon at 0°C. was added successively, 76 mg (0.10 mL, 0.72 mmol) of triethylamine,0.22 g (0.20 mL, 2.8 mmol) of acetylchloride and 7 mg (0.06 mmol) of4-dimethylaminopyridine. The reaction was stirred at room temperaturefor 90 h, diluted with water, and extracted with CH₂Cl₂ (2×). Thecombined organic layer was washed with brine, dried over MgSO₄, andconcentrated in vacuo. The title compound was obtained as an oil afterflash chromatography using silica, 10% ethyl acetate in hexane.

[0456]¹H NMR (CDCl₃, 300 M): δ_(—)1.31 (s, 3H), 1.43 (s, 3H), 1.46 (t,3H, J=7.1 Hz), 1.67-1.72 (m, 1H), 1.94-2.12 (m, 3H), 2.12 (s, 3H), 4.46(q, J=7.1 Hz, 2H), 6.06 (t, J=4.4 Hz, 1H), 7.51 (d, J=8.2 Hz, 1H), 7.61(d, J=2.0 Hz, 1H), 7.67 (dd, J=2.0, 8.2 Hz, 1H), 7.78 (dd J=1.7, 8.6 Hz,1H), 7.93 (d, J=8.6 Hz, 1H), 8.01 (d, J=8.7 Hz, 1H), 8.04 (s, 1H), 8.09(dd, J=1.7, 8.7 Hz, 1H), 8.62 (s, 1H).

[0457]Ethyl-6-[5,5-dimethyl-5,6-dihydro—naphthlen-8(7H)-anti-(O-methyl-oxime)-2yl]-naphthalen-2-oate(Compound B11)

[0458] A solution of 29 mg (0.08 mmol) ofethyl-6-[5,5-dimethyl-5,6-dihydro-naphthalen-8(7H)-one-2-yl]-naphthalen-2-oate(Compound B6), 27 mg (0.32 mmol) of methoxylamine hydrochloride and 68mg (0.5 mmol) of sodium acetate in 2.0 mL of EtOH and 0.5 mL oftetrahydrofuran was heated at 50° C. for 18 h. An additional 27 mg ofmethoxylamine hydrochloride was added and the mixture refluxed foranother 2 h. The mixture was concentrated in vacuo. The residue wasdiluted with water and extracted with EtOAc (2×). The combined organiclayer was dried over MgSO₄, and concentrated in vacuo. Flashchromatography silica, 5% ethyl acetate in hexanes) of the crudematerial afforded the title compound as a solid.

[0459]¹H NMR (CDCl₃, 300 MHz): 61.35 (s, 6H), _(—)1.46 (t, J=7.1 Hz,3H), 1.77 (t, J=6.9 Hz, 2H), 2.84 (t, J=6.9 Hz, 2H), 4.04 (s, 3H), 4.45(q, J=7.1 Hz, 2H), 7.47 (d, J=8.2 Hz, 1H), 7.67 (dd, J=2.1, 8.2 Hz, 1H),7.83 (dd, J=1.8, 8.5 Hz, 1H), 7.94 (d, J=8.6 Hz, 1H), 8.02 (d, J=8.6 Hz,1H), 8.07-8.10 (m, 2H), 8.34 (d, J=2.1 Hz, 1H), 8.63 (s, 1H).

[0460]6-[5,5-Dimethyl-5,6-dihydro—naphthlen-8(7H)-anti-(O-methyl-oxime)-2-yl]-2-naphthoicAcid (Compound B12)

[0461] Employing the same general procedure as for the preparation of(E)-4-[2-(5,6,7,8-tetrahydro-5,5-dimethyl-8-anti-(O-methyloxime)-2-naphthalenyl)ethenyl]-benzoicacid (Compound A4) 22 mg (0.06 mmol) ofethyl-6-[5,5-dimethyl-5,6-dihydro—naphthlen-8(7H)-anti-(O-methyl-oxime)-2-yl]-naphthalen-2-oate(Compound B11) was converted into the title compound (white solid).

[0462]¹H NMR (DMSO-D6, 300 MHz): δ_(—)1.30 (s, 6H), 1.72 (t, J=6.9 Hz,3H), 2.78 (t, J=6.9 Hz, 2H), 3.97 (s, 3H), 7.59 (d, J=8.2 Hz, 1H), 7.81(dd, J=2.1, 8.2 Hz, 1H), 7.89 (dd, J=1.8, 8.7 Hz, 1H), 8.00 (dd, J=1.7,8.6 Hz, 1H), 8.12 (d, J=8.7 Hz, 1H), 8.21-8.26 (m, 3H), 8.64 (s, 1H).

[0463] (5,6,7,8-Tetrahydro-5,5-dimethylnaphth-2-yl)boronic Acid

[0464] (Compound B13)

[0465] To a cold (−78° C.) solution of 2.02 g (8.4 mmol) of6-bromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene in 11.0 mL oftoluene, was added 4.6 g (6.8 mL, 10.9 mmol, 1.6 M in hexane) of n-BuLi.The resulting solution was stirred at −78° C. for 45 min. and then 2.40g (3.0 mL, 12.7 mmol) of triisopropylborate was dropwise added and thereaction stirred at room temperature for 12 h. The reaction was thendiluted with 10% HCl, and extracted with ether (2×). The combinedorganic layer was washed with brine, dried over MgSO₄, and concentratedin vacuo to give an oil. Recrystallization from hexane afforded thetitle compound as a white solid.

[0466]¹H NMR (CDCl₃, 300 MHz): 61.34 (s, 6H), 1.71 (m, 2H), 87 (m, 2H),1.89 (t, J=6.3 Hz, 2H), 7.47 (d, J=7.8 Hz, 1H), 7.89 (s, 1H), 7.99 (d,J=7.8 Hz, 1H).

[0467](5,5-Dimethyl-8-(t-butyldimethysilylloxy)-5,6,7,8-tetrahydro-naphth-2-yl)boronicAcid (Compound B14)

[0468] Employing the same general procedure as for the preparation of1,2,3,4-tetrahydro-1,1-dimethylnaphthyl-6-boronic acid (Compound B13)12.40 g (34 mmol) of6-bromo-1,2,3,4-tetrahydro-1,1-dimethyl-4-(t-butyldimethylsilyloxy)naphthaleneCompound B15) was converted into the title compound using 18.4 g (27.0mL, 43 mmol, 1.6 M in hexane) of n-BuLi and 9.37 g (11.50 mL, 50 mmol)of trisiopropylborate.

[0469]¹H NMR (CDCl₃, 300 MHz): δ_(—)0.22 (s, 3H), 0.28 (s, 3H), 0.98 (s,9H), 1.33 (s, 3H), 1.38 (s, 3H), 1.62-2.09 (m, 4H), 4.87 (m, 1H), 7.39(d, J=7.8 Hz, 1H), 8.07 (d, J=7.8 Hz, 1H), 8.29 (s, 1H).

[0470]2-(5,6,7,8-tetrahydro-5,5-dimethyl-8-(t-butyldimethylsilyloxy)naphthyl)bromide(Compound B15)

[0471] To a solution of 10.61 g (42 mmol) of6-bromo-1,2,3,4-tetrahydro-1,1-dimethyl-4-hydroxynaphthalene in 100 mLof methylene chloride stirring at 0° C. under argon, was added 5.23 g(7.20 mL, 52 mmol) of triethylamine, 0.55 g (4.5 mmol) of4-dimethylaminopyridine, and 7.71 g (51 mmol) of t-butyldimethylsilylchloride consecutively. The resulting solution was stirred at 0° C. toroom temperature for 90 hours. The reaction was then diluted with water,and extracted with methylene chloride (2×), the organic layers driedover NaSO₄, and concentrated in vacuo to give an oil. Purification wasdone using flash chromatography (silica, 4% ethyl acetate in hexane) togive the title compound as an oil.

[0472]¹H NMR (CDCl₃, 300 MHz): δ 0.15 (s, 3H), 0.18 (s, 3H), 0.95 (s,9H), 1.25 (s, 3H), 1.26 (s, 3H), 1.61-2.03 (m, 4H), 4.67 (m, 1H), 7.13(d, J=8.5 Hz, 1H), 7.30 (dd, J=2.1, 8.5 Hz, 1H), 7.51 (d, J=2.1 Hz, 1H).

[0473] 4,4-Dimethyl-7-acetyl-3,4-dihydronaphthalen-1(2H)-one (CompoundC1)

[0474] A solution of 4,4-dimethyl-7-bromo-3,4-dihydronaphthalen-1(2H)one(Compound G) (1.78 g, 7 mmol), 1-ethoxyvinyltributyltin (EVTB) (3.3 g,9.12 mmol), bis(triphenylphosphine)palladium(II)chloride (260 mg, 0.23mmol) in THF (25 mL) was refluxed for 24 h under argon atmosphere. Tothe reaction, additional EVTB (1.5 g, 4.1 mmol) andbis(triphenylphosphine)palladium(I)chloride (200 mg, 0.2 mmol) wereadded and the mixture was and refluxed for an additional 24 h. Thereaction mixture was cooled to room temeperature and 10% hydrochloricacid (10 ml) was added. After 10 min, the mixture was extracted withether (3×50 mL), the combined organic layer was washed with water (10mL), 10% sodiumbicarbonate (10 mL), brine (10 mL), dried with magnesiumsulfate. Solvent was removed under reduced pressure, and afterpurification by flash chromatography the title compound was obtained asa white solid.

[0475]¹H NMR (CDCl₃): δ 1.38 (s, 6H), 2.02 (t, J=6.54 Hz, 2H), 2.73 (t,J=6.54 Hz, 2H), 7.31 (d, J=8.43 Hz, 1H), 7.63 (dd, J=2.20, 8.43 Hz, 1H),8.13 (d, J=2.20 Hz, 1H).

[0476] Ethyl3-[4,4-dimethyl-3,4-dihydronaphthalen-1(2H)-one-7-yl]but-2(E)-enoate(Compound C2)

[0477] To a cold (−78° C.) slurry of sodiumhydride (336 mg, 14 mmol) inTHF (10 mL) was added triethylphosphonoacetate (3.58 g, 16 mmol).Cooling was discontinued and the mixture was stirred at ambienttemperature. After 30 min, a solution of4,4-dimethyl-7-acetyl-1,2,3,4-tetrahydronaphthalen-1(2H)-one (CompoundC1, 800 mg, 3.7 mmol) in THF (4 mL) was added and stirred for 36 h.

[0478] The reaction mixture was diluted with ether (120 mL), and washedwith water (10 mL), brine (10 mL), dried with magnesium sulfate. Solventwas removed under reduced pressure, chromatographic purification gavethe title compound as a colorless oil.

[0479]¹H NMR (CDCl₃): δ 1.33 (t, J=7.1 Hz, 3H), 1.41 (s, 6H), 2.04 (t,J=7.0 Hz, 2H), 2.59 (s, 3H), 2.76 (t, J=7.0 Hz, 2H), 4.23 (q, J=7.1 Hz,2H), 6.19 (s, 1H), 7.44 (d, J=8.3 Hz, 1H), 7.65 (dd, J=2.0, 8.3 Hz, 1H),8.15 (d, J=2.0 Hz, 1H).

[0480]3-[1-Hydroxy-4,4-dimethyl-1,2,3,4,-tetrahydronaphthalen-7-yl]but-2(E)-en-1-ol(Compound C3)

[0481] To a cold (−78° C.) solution of ethyl3-[4,4-dimethyl-1,2,3,4,-tetrahydronaphthalen-1(2H)one-7-yl]but-2(E)-enoate(Compound C2, 2.7 g, 9.4 mmol) in methylenechloride (20 mL) was addeddiisobutylaluminum hydride (DibAl—H, 1M solution in methylenechloride)(45 mL). The reaction was gradually warmed to −10° C. The reaction wasquenched by adding methanol (3 mL), water (10 mL), 10% hydrochoric acid(40 mL) and stirred for 10 min. The mixture was extracted withmethylenechloride (3×50 mL). The combined organic layer was washed withwater (10 mL), 10% sodiumbicarbonate (10 mL), brine (10 mL), dried withmagnesium sulfate. Solvent was removed under reduced pressure to obtainthe title compound as a white solid.

[0482]¹H NMR (CDCl₃): d 1.24 (s, 3H), 1.31 (s, 3H), 1.57-1.70 (m, 2H),1.82-1.96 (m, 2H), 2.03 (s, 3H), 4.29 (d, J=6.6 Hz, 2H), 4.68 (brs, 1H),5.95 (t, J=6.6 Hz, 1H), 7.28 (brs, 2H), 7.48 (s, 1H).

[0483]3-[4,4-Dimethyl-3,4,-dihydronaphthalen-1(2H)one-7-yl]but-2(E)-en-al(Compound C4)

[0484] To a solution of3-[1-hydroxy-4,4-dimethyl-1,2,3,4,-tetrahydronaphthalen-7-yl]but-2(E)en-1-ol(Compound C3, 1.5 g, 6.1 mmol) in dichloromethane (35 mL) was addedmanganese dioxide (9 g, 106 mmol) in two portions and stirred at roomtemperature for 48 h. After filtering out the manganese dioxide andremoving the solvent under reduced pressure the product was isolated asa white solid.

[0485]¹H NMR (CDCl₃): δ 1.41 (s, 6H), 2.03 (t, J=6.4 Hz, H, 2.58 (s,3H), 2.75 (t, J=6.4H, 2H), 6.41 (d, =7.7Hz, 1H), 7.48 (d, J=8.31, 1H),7.71 (dd, J=2.2, 8.31 Hz, 1H), 8.20 (d, J=2.2 Hz), 10.18 (d, J=7.7 Hz,1H).

[0486] Ethyl7-[4,4-dimethyl-3,4,-dihydronaphthalen-1(2H)one-7-yl]-3,7-dimethyl-hept-2(E),4(E), 6(E)trienoate (Compound C5)

[0487] To a cold (−78° C.) solution ofdiethyl-(E)-3-ethoxycarbonyl-2-methylalkylphosphonate in THF was addedn-BuLi (1.6 mmol solution in hexanes, 2.2 mL, 3.5 mmol) followed by3-[4,4-dimethyl-1,2,3,4,-tetrahydronaphthalen-1(2H)one-7-yl]but-2(E)-en-al(Compound C4, 300 mg, 1.24 mmol) in THF (2 mL). The mixture was stirredfor 16 h at −78° C. The mixture was treated with water and extractedwith ether (3×40 mL). The combined organic layer was washed with water(10 mL), brine (10 mL) and dried with MgSO₄. Solvent was removed underreduced pressure, the crude product was purified by columnchromatography, followed by HPLC to give the title compound as a solid.

[0488]¹H NMR (CDCl₃): δ 1.30 (t, J=7.1 Hz, 3H), 1.40 (s, 6H), 2.03 (t,J=6.8 Hz, 2H), 2.26 (s, 3H), 2.38 (s, 3H), 2.75 (t, J=6.8 Hz, 2H), 4.20(q, J=7.1 Hz, 2H), 5.82 (s, 1H), 6.41 (s, J=15.0 H), 1H), 6.64 (d,J=11.0 , 1H), 7.01 (dd, J=11.0, 15.0 Hz, 1H), 7.41 (d, J=8.2 Hz, 1H),7.66 (dd, J=2.0, 8.2 Hz, 1H), 8.14 (d, J=2.0 Hz).

[0489] 4,4-Dimethyl-7-acetyl-1-phenylthio-3,4-dihydronaphthalene(Compound C7)

[0490] Employing the procedure used for the preparation of4,4-dimethyl-7-acetyl-3,4-dihydronaphthalen-1(2H)-one (Compound C1) 1.2g, (3.5 mmol) of4,4-dimethyl-7-Bromo-1-phenylthio-3,4-dihydronaphthalene (Compound A35)was converted to the title compound.

[0491]¹H NMR (CDCl₃): δ 1.35 (s, 6H), 2.42 (d, J=4.8 Hz, 2H), 2.43 (s,3H), 6.59 (t, J=4.8 Hz, 1H), 7.10-7.27 (m, 4H), 7.32 (d, J=8.5 Hz, 1H),7.40 (d, J=8.1 Hz, 1H), 7.82 (dd, J=1.9, 8.1 Hz, 1H), 8.18 (d, J=1.9 Hz,1H).

[0492]3-[4,4-Dimethyl-1-phenylthio-3,4-dihydronaphthalen-7-yl]but-2-en(E)-nitrile(Compound C8)

[0493] Employing the procedure used for the preparation of ethyl3-[4,4-dimethyl-3,4-dihydronaphthalen-1(2Hone-7-yl]but-2(E)-enoate(Compound C2) instead using diethylcyanomethylphosphonate (1.77 g, 10mmol), sodium hydride (220 mg, 9 mmol) and4,4-dimethyl-7-acetyl-1-phenylthio-3,4-dihydronaphthalene (Compound C7,924 mg, 3 mmol) was converted to the title compound.

[0494]¹H NMR (CDCl₃): 1.34 (s, 6H), 2.30 (s, 3H), 2.42 (d, J=4.6 Hz,2H), 5.38 (s, 1H), 6.61 (t, J=4.6 Hz, 1H), 7.10-7.37 (m, 7H), 7.69 (d,J=1.9 Hz, 1H).

[0495]3-[4,4-Dimethyl-1-phenylthio-3,4-dihydronaphthalen-7-yl]but-2-en(E)-aldehyde(Compound C9)

[0496] To a cold (−78° C.) solution of 3-[4,4-dimethyl-1-phenylthio-3,4dihydronaphthalen-7-yl]but-2-en(E)-nitrile (Compound C5, 400 mg, 1.2mmol), in dichloromethane (10 mL) was added diisobutylaluminum hydride(DiBAl—H) (1M solution in dichloromethane, 2.5 mL, 2.5 mmol). Thereaction was warmed to −40° C. gradually over a period of 1 h. Then thereaction was quenched by adding methanol (1.5 mL), diluted with ether:ethylacetate (1:1, 100 mL), washed with 10% HCl (10 mL), water (10 mL),and brine (10 mL). The organic layer was dried (MgSO₄) and the solventwas removed under reduced pressure. The title compound was obtained as acolorless oil after silicagel chromatography.

[0497]¹H NMR (CDCL₃): δ 1.36 (s, 6H), 2.40 (d, J=1.3 Hz, 3H), 2.42 (d,J=4.7 Hz, 2H), 6.25 (dd, J=1.3, 7.9 Hz, 1H), 6.60 (t, J=4.7 Hz, 1H),7.10-7.43 (m, 7H), 7.81 (d, J=1.9 Hz, 1H), 10.11 (d, J=7.9 Hz, 1H).

[0498] Ethyl7-[4,4-dimethyl-1-(phenalthio)-3.4,-dihydronaphthalen-7-yl-3,7-dimethyl-hept-2(E),4(E), 6(E)trienoate (Compound C10)

[0499] Employing the procedure used for the preparation of ethyl7-[4,4-dimethyl-3,4,-dihydronaphthalen-1(2H)one-7-yl]-3,7-dimethyl-hept-2(E), 4(E), 6(E)trienoate (Compound C5) instead usingdiethyl-(E)-3-ethoxycarbonyl-2-methylalkylphosphonate (786 mg, 3 mmol),n-BuLi (2.8 mmol),3-[4,4-dimethyl-1-phenylthio-3,4-dihydronaphthalen-7-yl]but-2-en(E)-aldehyde(Compound C9, 280 mg, 0.84 mmol) was converted to the title compound.

[0500]¹H NMR (CDCl₃): δ 1.32 (t, J=7.1 Hz, 3H), 1.36 (s, 6H, 2.12 (s,3H), 2.38 (s, 3H), 2.41 (d, J=4.7 Hz, 2H), 4.20 (q, J=7.1 Hz, 2H), 5.82(s, 1H), 6.29 (d, J=14.8 Hz, 1H), 6.33 (d, J=9.9 Hz, 1H), 6.58 (t, J=4.7Hz, 1H), 6.96 (dd, J=9.9, 14.8 Hz, 1H), 7.12-7.38 (m, 7H), 7.74 (d,J=1.7 Hz, 1H).

[0501] Ethyl7-[4,4-dimethyl-1-phenylsulfonyl-3,4,-dihydronaphthalen-7-yl]-3,7-dimethyl-hept-2(E),4E), 6E)trienoate (Compound C11a)

[0502] Ethyl7-[4,4-dimethyl-1-phenylsulfoxide-3,4,-dihydronaphthalen-7-yl]-3,7-dimethyl-hept-2(E),4(E), 6(E)trienoate (Compound C11b) 9 To a cold (0° C.) solution ofethyl7-[4,4-dimethyl-1-phenylthio-3,4,-dihydronaphthalen-7-yl]-3,7-dimethyl-hept-2(E),4(E), 6(E)trienoate (Compound C10, 44 mg, 0.1 mmol) in dichloromethane(3 mL) was added m-chloroperoxybenzoic acid (approximately 60%concentration, 30 mg, 0.1 mmol). The mixture was stirred for 2 h at 0°C., diluted with dichloromethane (40 mL) and washed successively with10% sodiumbicarbonate (5 mL), water (5 mL) and brine (5 mL). The organiclayer was dried (MgSO₄) and the solvent was removed under reducedpressure. The title compounds were obtained after separation of themixture by silicagel chromatography.

[0503] Ethyl7-[4,4-dimethyl-1-phenylsulfonyl-3,4,-dihydronaphthalen-7-yl]-3,7-dimethyl-hept-2(E),4(E), 6(E)trienoate (Compound 11a)

[0504]¹H NMR (CDCl₃): 1.23 (s, 6H), 1.31 (t, J=7.1 Hz, 3H), 2.17 (s,3H), 2.39 (s, 3H), 2.51 (d, J=4.9 Hz, 2H), 4.20 (q, J=7.1 Hz, 2H), 5.84(s, 1H), 6.36 (d, J=15.1 Hz, 1H), 6.41 (d, J=13.0 Hz, 1H), 6.99 (dd,J=12.0, 15.1 Hz), 1H), 7.27 (d, J=1.7 Hz, 1H), 7.34 (dd, J=1.9, 8.2 Hz,1H), 7.45-7.60 (m, 4H, 7.93-8.0 (m, 3H).

[0505] Ethyl7-[4,4-dimethyl-1-phenylsulfoxide-3,4,-dihydronaphthalen-7-yl]-3,7-dimethyl-hept-2(E),4(E), 6(E)trienoate (Compound 11b)

[0506]¹H NMR (CDCl₃): δ 1.32 (s, 3H, 1.30 (s, 3H), 1.31 (t, J=7.1 Hz,3H), 2.15 (s, 3H), 2.38 (s, 3H), 2.50 (d, J=4.6 Hz, 2H), 4.19 (q, J=7.1Hz, 2H), 5.84 (s, 1H), 6.36 (d, J=15.0 Hz, 1H), 6.39 (d, J=11.6 Hz, 1H),6.90-7.04 (m, 2H), 7.24-7.32 (m, 2H), 7.41-7.50 (m 3H), 7.53 (d, J=1.8Hz, 1H), 7.74 (dd, J=2.5, 8.0 Hz, 2H).

[0507] Ethyl7-[4,4-dimethyl-1,2,3,4,-tetrahydronaphthalen-1-hydroxy-7-yl]-3,7-dimethyl-hept-2(E),4(E), 6(E)trienoate (Compound C13)

[0508] To cold (0° C.) solution of ethyl7-[4,4-dimethyl-3,4,-dihydronaphthalen-1(2H)one-7-yl]-3,7-dimethyl-hept-2(E),4(E), 6(E)trienoate (Compound C5, 6 mg, 0.02 mmol) in ether (3 mL) wasadded ZnBH₄ (0.5 M solution in ether, 0.5 mL). The mixture was stirredfor 30 min. and quenched the with water, diluted with ether (30 mL). Theorganic layer was washed with water (5 mL), 10% HCl (5 mL), water (5mL), 10% NaHCO₃ (5 mL) and brine (5 mL). The organic layer was driedwith MgSO₄, and the solvent was removed under reduced pressure to obtainthe title compound as a white solid.

[0509]¹H NMR (CDCl₃): δ 1.26 (s, 3H), 1.30 (t, J=7.1 Hz, 3H), 1.34 (s,3H), 1.58-1.70 (m, 1H), 1.82-1.95 (m, 2H), 2.05-2.15 (m, 1H), 2.25 (s,3H), 2.38 (s, 3H), 4.18 (q, J=7.1 Hz), 4.75 (brs, 1H), 5.81 (s, 1H),6.37 (d, J=15.1 Hz, 1H), 6.60 (d, J=11.2 Hz, 1H), 7.02 (dd, J=11.2, 15.1Hz, 1H), 7.31 (d, J=8.3 Hz, 1H), 7.39 (dd, J=2.1, 8.3 Hz, 1H).

[0510] Ethyl7-[4,4-dimethyl-3,4,-dihydronaphthalen-1-trifluoromethylsulfonyloxy-7-yl]-3,7-dimethyl-hept-2(E),4(E), 6(E)trienoate (Compound C14)

[0511] To a cold (−78° C.) stirring solution of ethyl7-[4,4-dimethyl-3,4,-dihydronaphthalen-1(2H)one-7-yl]-3,7-dimethyl-hept-2(E),δ 4(E), 6(E)trienoate (Compound C5, 190 mg, 0.55 mmol), in THF (10 mL)was added sodium bis(trimethylsilyl)amide (1M solution in THF, 0.5 mL,0.5 mmol). After 20 min.2-N,N-bis(trifluoromethylsulfonyl)amino-5-chloropyridine (216 mg, 0.6mmol) in THF (2 mL) was added, after another 20 min. the temparature wasincreased to −10° C. and the mixture was stirred at this temperature foranother 20 min. The reaction was quenched by adding aqueous NH₄Cl (10mL), extracted with ether (3×30 mL). The combined organic layer waswashed successively with water (10 mL) and brine (10 mL), dried withMgSO₄. The solvent was removed, and the resulting crude mixture waspurified by silicagel chromatography and HPLC to afford the titlecompound as a white solid.

[0512]¹H NMR (CDCl₃): δ 1.31 (t, J=7.1 Hz, 3H), 1.32 (s, 6H), 2.25 (s,3H), 2.39 (s, 3H), 2.43 (d, J=4.9, 2H), 4.19 (q, J=7.1 Hz, 2H), 5.83 (s,1H), 5.99 (t, J=4.9 Hz, 1H), 6.40 (d, J=15.0 Hz, 1H), 6.57 (d, J=11.3Hz, 1H), 7.01 (dd, J=11.3, 15.0 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.46(dd, J=1.9, 8.0 Hz, 1H), 7.47 (d, J=1.9 Hz, 1H).

[0513] Ethyl7-[4,4-dimethyl-3,4,-dihydronaphthalen-1-(2-thienyl)-7-yl]-3,7-dimethyl-hept-2(E),4(E), 6(E)trienoate (Compound C15)

[0514] To a cold (−78° C.) solution of thiophene (252 mg, 3 mmol) in THF(2 mL) was added t-BuLi (1.4 M solution in cyclohexane, 2 mL, 2.8 mmol)and the mixture was warmed to −30° C. over a period of 30 min. Themixture was recooled to −78° C. and a solution of zinc chloride (408 mg,3 mmol) in THF (1 mL) was added to it. The white turbid mixture waswarmed to ambient temperature and stirred for 30 min. This mixture wastransferred to a flask containing ethyl7-[4,4-dimethyl-3,4,-dihydronaphthalen-1-trifluoromethylsulfonyloxy-7-yl]-3,7-dimethyl-hept-2(E),4(E), 6(E)trienoate (Compound C14, 118 mg, 0.25 mmol), palladiumtetrakis(triphenylphosphine) (250 mg, 0.22 mmol) and THF (1 mL). Thereactants were heated to 50° C. for 3 h. and then the reaction wasquenched by adding aqueous NH₄Cl (10 mL). The reaction mixture wasextracted with ethylacetate (3×20 mL). The combined organic layer waswashed with water (10 mL) and brine (10 mL), dried with MgSO₄. Thesolvent was removed under reduced pressure and the title compound wasobtained as pale yellow solid after silicagel chromatography.

[0515]¹H NMR (CDCl₃): δ 1.29 (t, J=7.1 Hz), 1.33 (s, 6H), 2.18 (s, 3H),2.33 (d, J=4.8 Hz, 2H), 2.36 (s, 3H), 4.17 (q, J=7.1 H, 2H), 5.79 (s,1H), 6.21 (t, J=4.8 Hz, 1H) 6.33 (d, J=15.1 Hz, 1H), 6.48 (d, J=11.5 Hz,1H), 6.98 (dd, J=11.5, 15.1 Hz, 1H), 7.08 (br d, J=3.4 Hz, 2H),7.26-7.29 (m, 1H), 7.32-7.41 (m, 2H), 7.52 (d, J=1.6 Hz, 1H).

[0516] Ethyl7-[4,4-dimethyl-3,4,-dihydronaphthalen-1(2H)-(anti)(O-methyl-oxime)-7-yl]-3,7-dimethyl-hept-2(E),4(E), 6(E)trienoate (Compound C16)

[0517] To a solution of ethyl7-[4,4-dimethyl-3,4,-dihydronaphthalen-1(2H)one-7-yl]-3,7-dimethyl-hept-2(E),4(E), 6(E)trienoate (Compound C5, 25 mg, 0.07 mmol) in ethanol (2 mL)and THF (2 mL), was added sodium acetate trihydrate (103 mg, 0.75 mmol)followed by methoxylamine hydrochloride (42 mg, 0.5 mmol). The mixturewas stirred at ambient temperature for 16 h and diluted with ether (60mL). The ether layer was washed successively with 10% NaHCO₃ (5 mL),water (5 mL) and brine (10 mL). The organic layer was dried with MgSO₄and the solvent was removed under reduced pressure. After purificationby chromatography on silicagel the title compound was obtained as awhite solid

[0518]¹H NMR (CDCl₃): δ 1.29 (s, 6H), 1.30 (t, J=7.1 z, 3H), 1.72 (t,J=7.0 Hz, 2H), 2.27 (s, 3H), 2.39 (s, 3H), 2.80 (t, J=7.0 Hz, 2H), 4.03(s, 3H), 4.18 (q, J=7.1 Hz, 2H), 5.82 (s, 1H), 6.40 (d, J=15.0 Hz, 1H),6.60 (2, J=11.0 Hz, 1H), 7.03 (dd, J=11.0, 15.0 Hz, 1H), 7.33 (d, J=8.3Hz, 1H), 7.44 (dd, J=2.1 Hz, 8.3 Hz, 1H), 8.07 (d, J=2.1 Hz, 1H).

[0519] Ethyl 7-[4,4-dimethyl-3,4,-dihydronaphthalen-1(2H),-(anti)(carbethoxymethylenyl)-7-yl]-3,7-dimethyl-hept-2(E), 4(E),6(E)trienoate (Compound C17a)

[0520] Ethyl7-[4,4-dimethyl-3,4,-dihydronaphthalen-1(2H)-(syn)(carbethoxymethylenyl)-7-yl]-3,7-dimethyl-hept-2(E),4(E), 6(E)trienoate (Compound C17b)

[0521] To a cold (−78° C.) slurry of sodium hydride (24 mg, 1 mmol) inTHF (3 mL) was added triethylphosphonoacetate (300 mg, 1.4 mmol). Themixture was stirred for 30 min. at 0° C. To this mixture a solution ofethyl7-[4,4-dimethyl-3,4,-dihydronaphthalen-1(2H)one-7-yl]-3,7-dimethyl-hept-2(E),4(E), 6(E)-trienoate (Compound C5, 50 mg, 0.15 mmol) in THF (2 mL) wasadded and stirred at ambient temperature for 48 h. The reaction wasquenched by adding water (5 mL) and extracted with ethyl acetate (3×30mL). The combined organic layer was washed with water (5 mL), brine (5mL) and dried (MgSO₄). The solvent was removed under reduced pressureand the title compounds were obtained after silicagel chromatography andHPLC separation. Ethyl7-[4,4-dimethyl-3,4,-dihydronaphthalen-1(2H)-(anti)(carbethoxymethylenyl)-7-yl]-3,7-dimethyl-hept-2(E),4(E), 6(E)trienoate (Compound 17a)

[0522]¹H NMR (CDCl₃): δ 1.30 (s, 6H), 1.30 (t, J=7.1 Hz, 3H), 1.34 (t,J=7.1 Hz, 3H), 1.73 (t, J=6.6 Hz, 2H), 2.26 (s, 3H), 2.38 (s, 3H), 3.24(t, J=6.6 Hz, 2H), 4.13-4.28 (m, 4H), 5.82 (s, 1H), 6.31 (s, 1H), 6.40(d, J=15.0 Hz, 1H), 6.57 (d, J=1.5 Hz, 1H), 7.01 (dd, J=11.5, 15.0 Hz,1H), 7.35 (d, J=8.3 Hz, 1H), 7.46 (dd, J=1.9, 8.3 Hz, 1H), 7.66 (d,J=1.9 Hz, 1H). Ethyl7-[4,4-dimethyl-3,4,-dihydronaphthalen-1(2H)-(syn)(carbethoxymethylenyl)-7-yl]-3,7-dimethyl-hept-2(E),4(E), 6(E)trienoate (Compound C17b)

[0523]¹H NMR (CDCl₃) δ 1.25 (t, J=7.1 Hz, 3H), 1.28 (t, J=7.1 Hz, 3H),1.32 (s, 6H), 1.83 (t, J=6.5 Hz, 2H), 2.23 (s, 3H), 2.38 (s, 3H), 2.54(t, J=6.5 Hz, 2H), 4.12-4.25 (m, 4H), 5.81 (s, 2H, 6.38 (d, J=15.1 Hz,1H), 6.57 (d, J=11.0 Hz, 1H), 7.01 (dd, J=11.0, 15.1 Hz, 1H), 7.30 (d,J=8.3 Hz, 1H), 7.46 (dd, J=1.9, 8.3 Hz, 1H), 7.72 (d, J=1.9 Hz, 1H).

[0524]7-[4,4-Dimethyl-1,2,3,4,-tetrahydronaphthalen-1-hydroxy-7-yl]-3,7-dimethyl-hept-2(E),4(E), 6(E)trienoic acid (Compound C19)

[0525] To a solution of ethyl 7-[4,4-dimethyl-1,2,3,4,-tetrahydronaphthalen-1-hydroxy-7-yl]-3,7-dimethyl-hept-2(E), 4(E),6(E)trienoate (Compound C13, 35 mg, 0.1 mmol) in THF (3 mL) and methanol(1 mL), was added lithiumhydroxide (1M solution in water, 0.3 mL, 0.3mmol) and warmed to 60° C. for 6 h. The reaction mixture was dilutedwith ether: ethylacetate (1:1, 40 mL), acidified with 10% aqueous HCl topH 6. The organic layer was washed with water (5 mL), brine (5 mL) anddried (MgSO₄), and the solvent was removed under reduced pressure. Afterpurification by preparative TLC the title compound was obtained as apale yellow solid.

[0526]¹H NMR (CDCl₃): δ 1.26 (s, 3H), 1.34 (s, 3H), 1.55-1.65 (m, 1H),1.70-2.10 (m, 3H), 2.27 (s, 3H), 2.40 (s, 3H), 4.77 (t, J=5.6 Hz, 1H),5.84 (s. 1H), 6.41 (d, J=15.1 Hz, 1H), 6.62 (d, J=11.1 Hz, 1H), 7.08(dd, J=11.1, 15.1 Hz, 1H), 7.32 (d, J=8.3 Hz, 1H), 7.40 (dd, J=1.9, 8.3Hz, 1H), 7.57 (d, J=1.9H, 1H).

[0527]7-[4,4-Dimethyl-3,4,-dihydronaphthalen-1-(2-thienyl)-7-yl]-3,7-dimethyl-hept-2(E),4(E), 6(E)trienoic acid (Compound C20)

[0528] Employing the procedure used for the preparation of7-[4,4-dimethyl-1,2,3,4,tetrahydronaphthalen-1-hydroxy-7-yl]-3,7dimethyl-hept-2(E), 4(E), 6(E)trienoic acid (Compound C19), 20 mg (0.05mmol) of ethyl7-[4,4dimethyl-3,4,-dihydronaphthalen-1-(2-thienyl)-7-yl]-3,7-dimethyl-hept-2(E),4(E), 6(E)trienoate e (Compound C15) was converted to the titlecompound.

[0529]¹H NMR (CD₃COCD₃): δ 130 (s, 6H), 2.19 (s, 3H), 2.32 (d, J=4.8 Hz,2H), 2.35 (s, 3H), 5.84 (s, 1H), 6.22 (t, J=4.8 Hz, 1H), 6.47 (d, J=15.1Hz, 1H), 6.58 (d, J=1.0 Hz, 1H), 7.05-7.18 (m, 3H), 7.38-7.55 (m, 4H).

[0530] Ethyl7-[4,4-dimethyl-3,4,-dihydronaphthalen-1-cyano-7-yl]-3,7-dimethyl-hept-2(E),4(E), 6(E)trienoate (Compound C21)

[0531] To a solution of ethyl7-[4,4-dimethyl-3,4,-dihydronaphthalen-1-trifluoromethylsulfonyloxy-7-yl]-3,7-dimethyl-hept-2(E),4(E), 6(E)trienoate (Compound C14, 87 mg, 0.18 mmol) in THF (10 mL) wereadded tetrakis(triphenylphosphine)palladium (10 mg, 0.01 mmol) and zinccyanide(42 mg, 036 mmol). The mixture was heated to 50° C. for 1 h.Additional quantities of tetrakis(triphenylphosphine)palladium (10 mg,0.01 mmol) and zinc cyanide (42 mg, 0.36 mmol) were added and themixture heated to 50° C. for another 1 h. The reaction was quenched withwater (5 mL), extracted with ethyl acetate (2×20 mL), and the combinedorganic layer was washed with water, followed by brine. The organiclayer was dried (MgSO₄) and solvent removed under reduced pressure.After silicagel chromatography the title compound was isolated as asolid

[0532]¹H NMR (CDCl₃): δ 1.29 (s, 6H), 1.30 (t, J=7.1 Hz, 3H), 2.26 (s,3H), 2.39 (s, 3H), 2.41 (d, J=4.8 Hz, 2H), 4.18 (q, J=7.1 Hz, 2H), 5.83(s, 1H), 6.41 (d, J=15.0 Hz, 1H), 6.61 (d, J=11.0 Hz, 1H), 6.87 (t,J=4.8 Hz, 1H), 7.01 (dd, J=11.0, 15.0 Hz, 1H), 7.32 (d, J=8.2 Hz, 11H),7.44 (dd, J=2.0, 8.2 Hz, 1H), 7.57 (d, J=2.0 Hz, 1H).

[0533] Ethyl 7-[4,4-dimethyl-3,4-dihydro-1(2R)-syn-(O-ethyloxime)-naphth-7-yl]3,7-dimethyl-hepta-2(E),4(E),6(E)-trienoate (Compound22a)

[0534] Ethyl 7-[4,4-dimethyl-3,4-dihydro-1(2H)-anti-(O-ethyloxime)-naphth-7-yl]3,7-dimethyl-hepta-2(E),4(E),6(E)-trienoate 6(Compound C22b)

[0535] To a solution of ethyl7-[4,4-dimethyl-3,4-dihydronaphthalen-1(2H)one-7-yl]3,7-dimethyl-hepta-2(E),4(E),6(E)-trienoate(Compound C5, 128 mg, 0.4 mmol) in THF (10 mL) and ethanol (10 mL), wasadded O-ethylhydroxylamine hydrochloride (280 mg, 2.8 mmol), sodiumacetate trihydrate (600 mg, 4.4 mmol) and the mixture was stirred atambient temperature for 80 h. The reaction mixture was diluted withethyl acetate (50 mL) and washed with water (10 mL) and brine (50 mL).The organic phase was dried over MgSO₄ and then concentrated in vacuo toa yellow oil. Purification by column chromatography (silica, 10%EtOAc-hexane) followed by HPLC separation (partisil 10, 10%EtOAc-hexane) afforded the title compounds as white solid in the ratiosof 1 (syn): 7 (anti).

[0536] Ethyl 7-[4,4-dimethyl-3,4-dihydro-1(2H)-syn-(O-ethyloxime)-naphth-7-yl]3,7-dimethyl-hepta-2(E),4(E),6(E)-trienoate (CompoundC22a)

[0537]¹H NMR (CDCl₃): δ 1.27-1.39 (m, 12H), 1.88 (t, J=6.3 Hz, 2H), 2.25(s, 3H), 2.39 (s, 3H), 2.56 (t, J=6.5 Hz, 2H), 4.19 (m, 4H), 5.81 (s,1H), 6.34 (d, J=15.0 Hz, 1H), 6.57 (d, J=11.0 Hz, 1H), 7.03 (dd, J=11.4,15.0 Hz, 1H), 7.36 (d, J=8.4 Hz, 1H), 7.46 (dd, J=2.0, 8.6 Hz, 1H), 8.65(d, J=2.0 Hz, 1H).

[0538] Ethyl 7-[4,4-dimethyl-3,4-dihydro-1(2H)-anti-(O-ethyloxime)-naphth-7-yl]3,7-dimethyl-hepta-2(E),4(E),6(E)-trienoate (CompoundC22b)

[0539]¹H NMR (CDCl₃): δ 1.28-1.31 (m, 9H), 1.36 (t, J=8.2 Hz, 3H), 1.73(t, J=6.9 Hz, 2H) 2.27 (s, 3H), 2.40 (s, 3H), 2.82 (t, J=6.9 Hz, 2H),4.20 (q, J=7.2 Hz, 2H), 4.3 (q, J=7.1 Hz, 2H), 5.83 (s, 1H), 6.38 (d,J=15.1 Hz, 1H), 6.59 (d, J=11.0 Hz, 1H), 7.03 (dd, J=11.2, 15.1 Hz, 1H),7.32 (d, J=8.3 Hz, 1H), 7.42 (dd, J=2.1, 8.2 Hz, 1H), 8.09 (d, J=2.0 Hz,1H. 7-[4,4-dimethyl-3,4-dihydro-1(2H)-syn-(O-ethyloxime)-naphth-7-yl]3,7-dimethyl-hepta-2(E),4(E),6(E)-trienoic acid(Compound C24)

[0540] To a solution of ethyl7-[4,4-dimethyl-3,4-dihydro-1(2H)-syn-(O-ethyloxime)-naphth-7-yl]3,7-dimethyl-hepta-2(E),4(E),6(E)-trienoate (CompoundC22a, 7.8 mg, 0.02 mmol) in THF (1 mL) and ethanol (1 mL), was added 1Mlithium hydroxide (0.08 mL, 0.08 mmol) and the mixture was stirred atambient temparature or 8 days. Thereafter the reaction mixture wasdiluted with Et₂O :EtOAc (1:1, 10 ml) and acidified with 10% HC to pH 4.The organic layer was washed with water (5 mL), brine (10 ml), dried(MgSO₄) and the solvent was removed under reduced pressure.Recrystallization from EtOAc/hexane gave the title compound as a paleyellow solid.

[0541]¹H NMR (CDCl₃): δ 1.32 (s, 6H), 1.36 (t, J=7.1 Hz, 3H), 1.88(t,J=8.7 Hz, 2H), 2.25 (s, 3H), 2.39 (s, 3H), 2.55 (t, J=6.5 Hz, 2H), 4.20(q, J=7.0 Hz, 2H), 5.84 (s, 1H), 6.36 (d, J=15.0 Hz, 1H), 6.58 (d,J=11.0 Hz, 1H), 7.03 (dd, J=11.2, 15.1H, 1H), 7.36 (d, J=8.4 Hz, 1H),7.47 (dd, J=2.0, 8.6 Hz, 1H), 8.65 (d, J=2.0 Hz, 1H).

[0542] 7-[4,4-dimethyl-3,4-dihydro-1(2H)-anti-(O-ethyloxime)-naphth-7-yl]3,7-dimethyl-hepta-2(E),4(E),6(E)-trienoic acid(Compound C25)

[0543] To a solution of ethyl7-[4,4-dimethyl-3,4dihydro-1(2H)anti-(O-ethyloxime)-naphth-7-yl]3,7-dimethyl-hepta-2(E),4(E),6(E) -trienoate(Compound C22b, 40 mg, 0.1 mmol) in THF (2 mL) and ethanol (2 mL), wasadded 1M lithium hydroxide (2 mL, 2 mmol) and the mixture was stirred atambient temparature for 3 days and thereafter at 50° C. for 8 h. Thereaction mixture was diluted with Et₂O:EtOAc (1:1, 10 ml), and thenacidified with 10% HCl to pH 4. The organic layer was washed with water(5 mL), brine (10 ml), dried (MgSO₄) and the solvent was removed underreduced pressure. Recrystallization from EtOAc/hexane gave the titlecompound as a pale yellow solid.

[0544]¹H NMR (CDCl₃): δ 1.30 (s, 6H), 1.36 (t, J=7.0 Hz, 3H), 1.73 (t,J=7.0 Hz, 2H) 2.28 (s, 3H), 2.41 (s, 3H), 2.81 (t, J=6.9 Hz, 2H), 4.25(q, J=7.1 Hz, 2H), 5.86 (s, 1H), 6.41 (d, J=15.0 Hz, 1H), 6.60 (d,J=11.4 Hz, 1H), 7.03 (dd, J=11.4, 15.1 Hz, 1H), 7.32 (d, J=8.4 Hz, 1H),7.42 (dd, J=2.1, 8.4 Hz, 1H), 8.09 (d, J=2.0 Hz, 1H).

[0545] (−/+)Ethyl7-[4,4-dimethyl-1,2,3,4-tetrahydro-1-(O-methoxymethyl)-naphth-7-yl]3,7-dimethyl-hepta-2(E),4(E,)6(E)-trienoate(Compound C26)

[0546] To a solution of (−/+)ethyl7-[4,4-dimethyl-1,2,3,4-tetrahydro-1-hydroxy-naphth-7-yl]3,7-dimethyl-hepta-2(E),4(E),6(E)-trienoate(Compound C13, 67 mg, 0.19 mmol) in CH₂Cl₂ (1 mL) were addedN,N-diisopropylethylamine (91 mg, 1.1 mmol), chloromethyl methyl ether(294 mg, 2.3 mmol) and the mixture was stirred at ambient temparaturefor 12 h. Then the reaction mixture was diluted with water (5 mL) andEt₂O (25 mL) and washed with water (10 mL) and brine (10 mL). Theorganic phase was dried over MgSO₄ and concerntrated in vacuo to ayellow oil. Purification by flash column chromatography (silica, 10%EtOAc-hexane) followed by reverse phase HPLC separation (partisil 10ODS-2, 5% H₂O—AcCN) afforded the title compound as a pale yellow oil.

[0547]¹H NMR (CDCl₃): δ 1.24 (s, 3H), 1.29 (t, J=7.1 Hz, 3H), 1.34 (s,3H), 1.55-1.60(m, 1H), 1.91-2.05 (m, 3H), 2.24 (s, 3H), 2.38 (s, 3H),3.48(s, 3H), 4.16 (q, J=7.1 Hz, 2H), 4.65 (t, J=4.7 Hz, 1H), 4.76(d,J=7.0 Hz, 1H), 4.87(d, J=7.0 Hz, 1H), 5.80 (s, 1H), 6.33 (d, J=15.2 Hz,1H), 6.55 (d, J=11.5 Hz, 1H), 7.01 (dd, J=11.1, 15.0 Hz, 1H), 7.31 (d,J=8.3 Hz, 1H), 7.37 (dd, J=2.1, 8.4 Hz, 1H), 7.43 (d, J=2.1 Hz, 1H).

[0548] (+/−)7-[4,4-dimethyl-1,2,3,4-tetrahydro-1-(O-methoxymethyl)-naphth-7-yl]3,7-dimethyl-hepta-2(E),4(E),6(E)-trienoicacid (Compound C27)

[0549] Employing the same general procedure as for the preparation of7-[4,4-dimethyl-3,4-dihydro-1(2H)-anti-(O-ethyloxime)-naphth-7-yl]3,7-dimethyl-hepta-2(E),4(E),6(E)-trienoic acid(Compound C25), (−/+)ethyl7-[4,4-dimethyl-1,2,3,4-tetrahydro-1-(O-methoxymethyl)-naphth-7-yl]3,7-dimethyl-hepta-2(E),4(E),6(E)-trienoate(Compound C26, 20 mg, 0.05 mmol) was converted into the title compound(white solid).

[0550]¹H NMR (acetone-d₆): δ 1.23 (s, 3H), 1.30 (s, 3H), 1.55-1.60 (m,1H), 1.89-1.97 (m, 3H), 2.26 (s, 3H), 2.36 (s, 3H), 3.40 (s, 3H), 4.59(t, J=3.9 Hz, 1H), 4.72 (d, J=6.9 Hz, 1H), 4.81 (d, J=17.0 Hz, 1H), 5.85(s, 1H), 6.49 (d, J=15.1 Hz, 1H), 6.66 (d, J=11.3 Hz, 1H), 7.12 (dd,J=11.1, 15.1Hz, 1H), 7.36 (d, J=8.3 Hz, 1H), 7.43 (dd, J=2.1, 8.3 Hz,1H), 7.49 (d, J=2.0 Hz, 1H).

[0551] Ethyl7-[4,4-dimethyl-3,4-dihydro-1-(trimethylsiloxy)-naphth-2-yl]3,7-dimethyl-hepta-2(E),4(E),6(E)-trienoate(Compound C28)

[0552] To a solution of ethyl7-[4,4-dimethyl-3,4-dihydronaphthalen-1(2H)one-7-yl]3,7-dimethyl-hepta-2(E),4(E),6(E)-trienoate(Compound C5, 114 mg, 0.33 mmol) in anhydrous THF (10 mL) was addedsodium bis-(trimethylsilyl) amide (0.36 ml, 0.36 mmol) at −78° C. underargon. The reaction was stirred at −78° C. for 20 minutes. To thisreaction solution was then added a solution of trimethylsilylchloride(70.8 mg, 0.65 mmol) in HMPA (0.1 mL) and anhydrous THF (S ml) at −78°C. The reaction was allowed to stir at −78° C. for 2 h. Then thereaction mixture was diluted with Et₂O (25 mL) and washed with water (10mL), brine (10 mL). The organic phase was dried over MgSO₄ andconcerntrated in vacuo to a yellow oil. The product was purified byflash column chromatography (silica, 10% EtOAc-hexane) to afford thetitle compound as a pale yellow oil.

[0553]¹H NMR (acetone-d₆): δ 0.26 (s, 9H), 1.23 (t, J=7.1 Hz, 3H), 1.26(s, 6H), 2.25 (m, 5H), 2.37 (m, 3H), 4.08 (q, J=7.1 Hz, 2H), 5.15 (t,J=4.6 Hz, 1H), 5.83 (s, 1H), 6.48 (d, J=15.1 Hz, 1H), 6.65 (d, J=11.0Hz, 1H), 7.13 (dd, J=11.1, 15.0 Hz, 1H), 7.26 (d, J=8.1 Hz, 1H), 7.40(dd, J=2.1, 8.1 Hz, 1H), 7.60 (d, J=2.1 Hz, 1H).

[0554] (+/−)Ethyl7-[4,4-dimethyl-1,2,3,4-tetrahydro-1(RS)-(2′(RS)-tetrahydropyranoxy)-3,7-dimethyl—naphth-2-yl]hepta-2(E),4(E),6(E)-trienoate(Compound C29a)

[0555] (+/−)Ethyl7-[4,4-dimethyl-1,2,3,4-tetrahydro-1(RS)-(2′(SR)-tetrahydropyranoxy)-3,7-dimethyl-naphth-2-yl]hepta-2(E),4(E),6(E)-trienoate(Compound C29b)

[0556] To a solution of (−/+)ethyl7-[4,4-dimethyl-1,2,3,4-tetrahydro-1-hydroxy-naphth-7-yl]3,7-dimethyl-hepta-2(E),4(E),6(E)-trienoate (Compound C13,110 mg, 0.3 mmol) in anhydrous (CH₂Cl₂ (2 mL) was added3,4-dihydro-2H-pyran (62 mg, 0.7 mmol) followed by pyridiniump-toluenesulfonate (10 mg, 0.04 mmol). The reaction mixture was stirredat ambient temperature for 24 h. The reaction mixture was diluted withEt₂O (20 mL) and washed successively with saturated NaHCO₃ (10 mL),water(10 mL) and brine (10 mL). The organic phase was dried over MgSO₄ andconcerntrated in vacuo to a yellow oil. Purification by flash columnchromatography (silica, 15% EtOAc-hexane) followed by reverse phase HPLCseparation (partisil 10 ODS-2, 5% H₂O—AcCN) afforded the title compoundsas pale yellow oils.

[0557] (+/−)Ethyl7-[4,4-dimethyl-1,2,3,4-tetrahydro-1(RS)-(2′(RS)-tetrahydropyranoxy)-3,7-dimethyl—naphth-2-yl]hepta-2(E),4(E),6(E)-trienoate(Compound C29a)

[0558]¹H NMR (CDCl₃): δ 1.25-1.31 (m, 9H), 1.52-2.03 (m, 10H), 2.24 (s,3H), 2.38 (s, 3H), 3.50-3.60 (m, 1H), 4.01-4.07 (m, 1H), 4.12 (q, J=7.1Hz, 2H), 4.77 (t, J=4.5 Hz, 1H), 4.94 (t, J=3.5 Hz, 1H), 5.80 (s, 1H),6.32 (d, J=15.0 Hz, 1H), 6.56 (d, J=11.5 Hz, 1H), 7.02 (dd, J=11.1, 15.0Hz, 1H), 7.28 (d, J=8.3 Hz, 1H), 7.36 (dd, J=2.1, 8.3 Hz, 1H), 7.62 (d,J=2.0 Hz, 1H).

[0559] (+/−)Ethyl7-[4,4-dimethyl-1,2,3,4-tetrahydro-1(RS)-(2′(SR)-tetrahydropyranoxy)-3,7-dimethyl—naphth-2-yl]hepta-2(E),4(E),6(E)-trienoate(Compound C29b)

[0560]¹H NMR (CDCl₃): δ 1.25-1.32 (m, 9H), 1.52-2.08 (m, 10H), 2.45 (s,3H), 2.38 (s, 3H), 3.54-3.61 (m, 1H), 3.97-4.03 (m, 1H, 4.14 (q, J=7.1Hz, 2H), 4.68 (t, J=5.0 Hz, 1H), 4.87 (t, J=4.4 Hz, 1H), 5.81 (s, 1H),6.34 (d, J=15.2 Hz, 1H), 6.54 (d, J=11.0 Hz, 1H), 7.01 (dd, J=11.2, 15.1Hz, 1H), 7.30-7.40 (m, 3H)

[0561](+/−)₇-[4,4-Dimethyl-1,2,3,4-tetrahydro-1(RS)-(2′(RS)-tetrahydropyranoxy)-3,7-dimethyl-naphth-2-yl]hepta-2E),4(E),6(E)-trienoicacid (Compound C31)

[0562] Employing the same general procedure as for the preparation of7-[4,4-dimethyl-3,4-dihydro-1(2H)-anti-(O-ethyloxime)-naphth-7-yl]3,7-dimethyl-hepta-2(E),4(E),6(E)-trienoic acid(Compound C25), (+/−)ethyl7-[4,4-dimethyl-1,2,3,4-tetrahydro-1(RS)-(2′(RS)-tetrahydropyranoxy)-3,7-dimethyl—naphth-2-yl]hepta-2(E),4(E),6(E)-trienoate(Compound C29a, 15 mg, 0.03 mmol) was converted into the title compound(white solid).

[0563]¹H NMR (acetone-d₆): δ 1.24 (s, 3H) 1.29 (s, 3H), 1.52-2.03 (m,10H), 2.26 (s, 3H), 2.37 (s, 3H), 3.56-3.61 (m, 1H), 3.99-4.03 (m, 1H),4.70 (t, J=4.5 Hz, 1H), 4.91 (t, J=3.7 Hz, 1H), 5.80 (s, 1H), 6.49 (d,J=15.0 Hz, 1H), 6.66 (d, J=11.3 Hz, 1H), 7.13 (dd, J=11.1, 15.0 Hz, 1H),7.34 (d, J=8.3 Hz, 1H), 7.42 (dd, J=2.1, 8.3 Hz, 1H), 7.63 (d, J=2.0 Hz,1H).

[0564]7-Acetyl-1(2H)-(propyliden-2-yl)-3,4-dihydro-4,4-dimethylnaphthalene(Compound C33)

[0565] To a solution of7-bromo-1(2H)-(propyliden-2-yl)-3,4-dihydro-4,4-dimethylnaphthalene(Compound A37, 698 mg, 2.5 mmol) in anhydrous THF (15 mL) was added(1-ethoxyvinyl)tributyltin (1.8 g, 5 mmol) andbis(triphenylphosphine)palladium(II) chloride (20 mg). The resultantmixture was refluxed under argon atmosphere for 24 h. The reactionmixture was cooled to ambient temperature and quenched with 10% HCl(5mL), stirred for 20 mimutes and extracted with Et₂O (3×20 mL). Theorganic layer was washed with water (10 mL), saturated NaHCO₃ (10 mL),brine (10 mL) and dried over MgSO₄. The crude material was purified byflash column chromatography (silica, 5% EtOAc-hexane) to afford thetitle compound as a colorless oil.

[0566]¹H NMR (CDCl₃): δ 1.25 (s, 6H), 1.60 (t, J=6.9 Hz, 2H, 1.84 (s,3H), 1.97 (s, 3H), 2.49 (t, J=6.9 Hz, 2H), 2.57 (s, 3H), 7.35 (d, J=8.3Hz, 1H), 7.73 (dd, J=2.0, 8.2 Hz, 1H), 7.85 (d, J=1.9 Hz, 1H).

[0567]3-[1(2H.)-(Propyliden-2-yl))-3,4-dihydro-4,4-dimethylnaphthalen-7-yl]but-2(E)-en-nitrile(Compound C34)

[0568] To a slurry o NaH (117 mg, 4.8 mmol ) in anhydrous THF (10 mL)was added a solution of ethylcyanomethylphosphonate (947 mg, 5.4 mmol)in THF (2 mL) at −78° C. under argon atmosphere. The reaction wasallowed to warm to ambient temperature and a solution of7-acetyl-1(2H)-(propyliden-2-yl)-3,4-dihydro-4,4-dimethylnaphthalene(Compound C33, 394 mg, 1.6 mmol) in 5 mL of THF was added dropwise. Theresultant reaction was stirred for 16 h at ambient temperature andquenched with water (5 mL). After extraction with EtOAc (2×10 mL), thecombined organic layer was dried over MgSO₄, and concentrated in vacuoThe crude product was purified by flash column chromatography (silica,5% EtOAc-hexane) to afford the title compound as a colorless oil.

[0569]¹H NMR (CDCl₃): δ 1.24 (s, 6H), 1.60 (t, J=7.0 Hz, 2H), 1.85 (s,3H), 1.96 (s, 3H), 2.45 (s, 3H), 2.49 (t, J=6.8 Hz, 2H), 5.59 (s, 1H),7.24-7.35 (m, 3H).3-[1(2H)-(Propyliden-2-yl)-3,4-dihydro-4,4-dimethylnaphthalen-7-yl]but-2(E)-en-aldehyde(Compound C35)

[0570] To a solution of3-[1(2H)-(propyliden-2-yl)-3,4-dihydro-4,4-dimethylnaphthalen-7-yl]but-2(E)-en-onitrile(Compound C34, 311 mg, 1.2 mmol) in anhydrous CH₁Cl₂ (10 ml) was added asolution of diisobutylaluminum hydride (1M in CH₂Cl₂) (2.8 ml, 2.8 mmol)dropwise at −78° C., under argon atmosphere. The reaction was allowed tostir at −78° C. for 6 h. A mixture of H₂O (10 ml) and CH₂Cl₂ (10 ml) wasadded and the resultant gel was filtered. The filtrate was concentratedin vacuo to a yellow oil. Purification by flash column chromatography(silca, 10% EtOAc-hexane) afforded the title compound as a pale yellowoil.

[0571]¹H NMR (CDCl₃): δ 1.26 (s, 6H, 1.62 (t, J=7.0 Hz, 2H), 1.86 (s,3H), 1.98 (s, 3H), 2.50 (t, J=6.9 Hz, 2H, 2.57 (s, 3H), 6.40 (d, J=9.3Hz, 1H), 7.35-7.39 (m, 2H), 7.45 (d, J=1.9 Hz, 1H), 10.17 (d, J=7.9 Hz,1H).

[0572]Ethyl-7-[1(2H)-(propyliden-2-yl)-3,4-dihydro-4,4-dimethyl-naphthalen-7-yl]-3,7-dimethyl-hept-2(E),4(E),6(E)-trienoate(Compound C36)

[0573] Employing the same general procedure as for the preparation ofethyl7-[4,4-dimethyl-3,4-dihydronaphthalen-1(2H)one-7-yl]3,7-dimethyl-hepta-2(E),4(E),6(E)-trienoate(Compound C5), 3-[1(2H)-(propyliden-2-yl)-3,4-dihydro-4,4-dimethylnaphthalen-7-yl]but-2(E)-en-aldehyde(Compound C35, 178 mg, 0.6 mmol) was converted into the title compound(pale yellow thick syrup).

[0574]¹H NMR (CDCl₃): δ 1.24 (s, 6H), 1.27 (t, J=7.0 Hz, 3H), 1.60 (t,J=6.9 Hz, 2H), 1.84 (s, 3H), 1.98 (s, 3H), 2.24 (s, 3H), 2.37 (s, 3H),2.48 (t, J=6.7 Hz, 2H), 4.14 (q, J=7.1 Hz, 2H), 5.79 (s, 1H), 6.33 (d,J=14.9 Hz, 1H), 6.54 (d, J=10.9 Hz, 1H), 6.98 (dd, J=11.0, 15.0 Hz, 1H),7.25-7.28 (m, 2H), 7.36 (s, 1H).

[0575]7-Bromo-1(2H)-(phenylbenzyliden-yl)-3,4-dihydro-4,4-dimethylnaphthalene(Compound C37)

[0576] Employing the same general procedure as for the preparation of7-bromo-1(2H)-(propyliden-2-yl)-3,4-dihydro-4,4-dimethylnaphthalene(Compound A37), 7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one(Compound G, 1.0 g, 3.96 mmol) was converted into the title compound(white solid) using titanium trichloride (5 g, 32 mmol), lithium wire(0.7 g, 100 mmol) and benzophenone (800 mg, 4.4 mmol).

[0577]¹H NMR (CDCl₃): δ 1.31 (s, 6H), 1.66 (t, J=6.6 Hz, 2H, 2.52 (t,J=6.8 Hz, 2H), 6.92 (d, J=1.7 Hz, 1H), 6.98-7.00 (m, 2H), 7.15-7.21 (m,6H), 7.25-7.36 (m, 4H).

[0578]7-Acetyl-1(2H)-(phenylbenzyliden-yl)-3,4-dihydro-4,4-dimethylnaphthalene(Compound C38)

[0579] Employing the same general procedure as for the preparation of7-acetyl-1(2H)-(propyliden-2-yl)-3,4-dihydro-4,4-dimethylnaphthalene(Compound C33),7-bromo-1(2H)-(phenylbenzyliden-yl)-3,4-dihydro-4,4-dimethylnaphthalene(Compound C37, 255 mg, 0.63 mmol) was converted into the title compound(colorless oil) using (1-ethoxyvinyl)tributyltin (353 mg, 0.97 mmol) andbis(triphenylphosphine)palladium(II) chloride (20 mg).

[0580]¹H NMR (CDCl₃): δ 1.34 (s, 6H), 1.70 (t, J=6.4 Hz, 2H), 1.99 (s,3H), 2.57 (t, J=6.7 Hz, 2H), 7.01-7.04 (m, 2H), 7.12-7.45 (m, 10H), 7.65(dd, J=1.9, 8.3 Hz, 1H).

[0581]3-(1(2H)-(phenylbenzylidenyl)-3,4-dihydro-4,4-dimethylnaphth-7-yl)-but-2(E)-enonitrile(Compound C39)

[0582] Employing the same general procedure as for the preparation of3-(1(2H)-(propyliden-2-yl)-3,4-dihydro-4,4-dimethylnaphthyl)but-2(E)-enonitrile(Compound C34), the7-acetyl-1(2H)-(phenylbenzylidenyl)-3,4-dihydro-4,4-dimethylnaphthalene(Compound 38, 206 mg, 0.56 mmol) was converted into the title compound(colorless oil) using 327 mg (1.85 mmol) of ethylcyanomethylphosphonateand 40.3 mg (1.68 mmol) of sodium hydride.

[0583]¹H NMR (CDCl₃): δ 1.34 (s, 6H), 1.70 (t, J=6.3 Hz, 2H), 2.03 (s,3H), 2.57 (t, J=6.8 Hz, 2H), 4.88 (s, 1H), 7.01 (dd, J=2.0, 7.3 Hz, 2H),7.14-7.37 (m, 11H).

[0584] 3-(1(2H)-(phenylbenzylidenyl)-3,4-dihydro-4,4-dimethylnaphth-7-yl)-but-2(E)-enaldehyde(Compound C40)

[0585] Employing the same general procedure as for the preparation of3-(1(2H)-(propyliden-2-yl)-3,4-dihydro-4,4-dimethylnaphthyl)-but-2(E)-enaldehyde(Compound C35),3-(1(2H)-phenylbenzylidenyl)-3,4-dihydro-4,4-dimethylnaphth-7-yl)-but-2-enonitrile(Compound C39, 156 mg, 0.40 mmol) was converted into the title compound(pale yellow solid) using 0.9 ml (0.88 mmol) of diisobutylaluminumhydride (1M in CH₂Cl₂).

[0586]¹H NMR (CDCl₃): δ 1.35 (s, 6H), 1.70 (t, J=6.5 Hz, 2H), 2.04 (s,H), 2.57 (t, J=6.7 Hz, 2H), 5.88 (d, J=7.7 Hz, 1H), 7.02 (dd, J=1.5, 7.4Hz, 2H), 7.12-7.36 (m, 11H), 9.98 (d, J=7.8 Hz, 1H).

[0587] Ethyl7-[4,4-dimethyl-3,4-dihydro-1(2H)-(phenylbenzylidenyl)-naphth-7-yl]-3,7-dimethyl-hepta-2(E),4(E),6(E)-trienoate(Compound C41)

[0588] Employing the same general procedure as for the preparation ofethyl7-[4,4-dimethyl-3,4-dihydronaphthalen-1(2H)one-7-yl]3,7-dimethyl-hepta-2(E),4(E),6(E)-trienoate(Compound C5),3-(1(2H)-(phenylbenzylidenyl)-3,4-dihydro-4,4-dimethylnaphth-7-yl)-but-2(E)-enaldehyde(Compound C40, 101 mg, 0.26 mmol) was converted into the title compound(pale yellow thick oil).

[0589]¹H NMR (CDCl₃): δ 1.28 (t, J=7.1 Hz, 3H), 1.34 (s, 6H), 1.69 (t,J=6.3 Hz, 2H, 1.85 (s, 3H), 2.32 (s, 3H), 2.54 (t, J=6.9 Hz, 2H, 4.14(q, J=7.1 Hz, 2H), 5.74 (d, J=8.7 Hz, 1H), 5.77 (s, 1H), 6.15 (d, J=14.9Hz, 1H), 6.80 (dd, J=11.2, 15.0 Hz, 1H), 7.04-7.36 (m, 13H).

[0590] 7-Bromo-1-(1,1-dimethylethyl)-3,4-dihydro-4,4-dimethylnaphthalene(Compound C42)

[0591] In a flame dried round bottom flask7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound G, 2.0 g,7.93 mmol) was dissolved in anhydrous THF (50 ml) and3,4,5,6,-tetrahydro-2(H)-pyrimidinone (DMPU) (11.5 ml, 95.16 mmol) wasadded, under argon atmosphere. The reaction was then cooled to −20° C.and a solution of t-butyl magnesium chloride (16 ml, 31.7 mmol) (2 M inEt₂O) was added dropwise and stirred at −20° C. for 2 h and at ambienttemperature for 1 h, under argon atmosphere. The reaction was quenchedat 0° C. with saturated ammonium chloride solution (20 ml) and extractedwith EtOAc (2×50 ml). The combined extract was washed with water (20ml), brine (20 ml) and dried over MgSO₄. The solvent was evaporatedunder reduced pressure to afford a yellow oil. To this yellow oil wereadded MeOH (50 ml) and p-tolylsulfonic acid (100 mg). The resultantreaction solution was heated in an oil bath (60° C.) for 3 h. Thereaction was cooled and quenched with water (20 ml), extracted withEtOAc (2×(50 ml). The combined extract was washed with saturated NaHCO₃(20 ml), water (20 ml), brine (20 ml), and dried over MgSO₄. The solventwas concentrated in vacuo and the title compound was obtained as acolorless oil after purification by flash chromatography (silica,hexane).

[0592]¹H NM (CDCl₃): δ 1.17 (s, 6H), 1.32 (s, 9H), 2.10 (d, J=5.0 Hz,2H), 5.95 (t, J=4.9 Hz, 1H), 7.13 (d, J=8.3 Hz, 1H), 7.24 (dd, J=2.1,8.3 Hz, 1H), 7.74 (d, J=2.0 Hz, 1H.

[0593]7-Acetyl-1-(1,1-dimethylethyl)-3,4,-dihydro-4,4-dimethylnaphthalene(Compound C43)

[0594] Employing the same general procedure as for the preparation of7-acetyl-1 (2H) -(propyliden-2-yl)-3,4-dihydro-4,4-dimethylnaphthalene(Compound C33),7-bromo-1-(1,1-dimethylethyl)-3,4-dihydro-4,4-dimethylnaphthalene(Compound C42, 539 mg, 1.84 mmol) was converted into the title compound(white solid), using (1-ethoxyvinyl)tributyltin (2.6 g, 7.36 mmol) andbis(triphenylphosphine)palladium(II) chloride (80 mg).

[0595]¹H NMR (CDCl₃): δ 1.25 (s, 6H), 1.39 (s, 4.9H), 2.16 (d, J=0.9 Hz,2H), 2.60 (s ,3H), 6.00 (t, J=4.9 Hz, 1H), 7.39 (d, J=8.1Hz, 1H), 7.75(dd, J=1.7, 8.0 Hz, 1H), 8.29 (d, J=1.8 Hz, 1H).

[0596]3-[1-(1,1-dimethylethyl)-3,4-dihydro-4,4-dimethyl-naphthl]-2-but-2(E)-enonitrile(Compound C44)

[0597] Employing the same general procedure as for the preparation of3-(1-propylidene)-1,2,3,4-tetrahydro-4,4-dimethylnaphthyl)but-2(E)-enonitrile(Compound C34),7-acetyl-1-(1,1-dimethylethyl)-3,4-dihydro-4,4-dimethylnaphthalene(Compound C43, 326 mg, 1.26 mmol) was converted into the title compound(white solid) using 742 mg (4.19 mmol) of ethylcyanomethylphosphonateand 91 mg (3.80 mmol) of sodium hydride.

[0598]¹H NMR (CDCl₃): δ 1.22 (s, 6H), 1.36 (s, 9H), 2.14 (d, J=4.9 Hz,2H), 2.47 (s ,3H), 5.58 (s, 1H), 6.00 (t, J=4.9 Hz, 1H), 7.26 (dd,J=2.0, 8.2 Hz, 1H), 7.32 (d, J=8.1 h, 1H), 7.73 (d, J=1.9 Hz, 1H).

[0599] 3-[1-(1,1-dimethylethyl)-3,4-dihydro-4,4dimethyl-naphth-7-yl-but-2(E)-enaldehyde (Compound C45)

[0600] Employing the same general procedure as for the preparation of3-(1-propylidene)-1,2,3,4-tetrahydro-4,4-dimethylnaphthyl)-but-2(E)-enaldehyde(Compound C35),(E)-3-(1-(1,1-dimethylethyl)-3,4-dihydro-4,4-dimethylnaphthyl)-but-2)E)-enonitrile(Compound C45, 256 mg, 0.95 mmol) was converted into the title compound(pale yellow solid) using 2.8 ml (2.84 mmol) of diisobutylaluminumhydride (IM in CH₂Cl₂).

[0601]¹H NMR (CDCl₃): δ 1.25 (s, 6H), 1.30 (s, 9H), 2.16 (d, J=5.0 Hz,2H), 2.60 (s, 3H), 6.01 (t, J=4.9H, 1H), 6.41 (d, J=7.8 Hz, 1H), 7.38(m, 2H), 7.86 (s, 1H), 10.19 (d, J=8.0 Hz, 1H).

[0602] Ethyl7-[4,4-dimethyl-3,4-dihydro-1-(1,1-dimethylethyl)-naphth-7yl]-3,7-dimethyl-hepta-2(E),4(E),6(E)-trienoate(Compound C46)

[0603] Employing the same general procedure as for the preparation ofethyl3,7-dimethyl-7-[5,5-dimethyl-5,6,7,8-tetrahydro-8-oxo-naphth-2-yl]hepta-2(E),4(E),6(E)-trienoate(Compound C5,(E)-3-[1-(1,1-dimethylethyl)-3,4-dihydro-4,4-dimethyl-naphthyl]-2-butene-1aldehyde(Compound C45, 82.6 mg, 0.29 mmol) was converted into the title compound(pale yellow solid).

[0604]¹H NMR (CDCl₃): δ 1.24 (s, 6H), 1.28 (t, J=7.1 Hz, 3H), 1.39 (s,9H, 2.15 (d, J=4.9 Hz, 2H), 2.28 (s, 3H), 2.40 (s, 3H), 4.15 (q, J=7.1Hz, 2H), 5.83 (s, 1H), 5.97 (t, J=4.9 Hz, 1H), 6.36 (d, J=15.2 Hz, 1H),6.54 (d, J=11.5 Hz, 1H), 7.00 (dd, J=11.1, 15.0 Hz, 1H), 7.31 (s, 2H),7.78 (s, 1H).

[0605] (+/−) Ethyl4-[(5,5-dimethyl-8-hydroxy-8-carbethoxymethyl-5,6,7,8-tetrahydronaphth-2-yl)azo]benzoate(Compound D1)

[0606] To a refluxing solution of zinc dust (0.15 g, 20 mesh, activatedprior to use by washing with 2% of hydrochloric acid, water, 95%ethanol, acetone and anhydrous ether, then dried in vacuum for severalhours) in 6 ml of dry benzene was slowly added a mixture of bromo ethylacetate (0.082 ml, 0.74 mmol) and ethyl4-[(5,5-dimethyl-5,6-dihydro-naphthalen-8(7H)-one-2-yl)azo]benzoate(Compound D10, 0.13 g, 0.371 mmol) in 6 ml of dry benzene. The resultingmixture was refluxed for 2 h then cooled to room temperature. Theprecipitate was filtered through celite and the filtrate was washed withcold 15% sulfuric acid. The organic phase was washed with saturatedsodium bicarbonate, brine, dried over Na₂SO₄, filtered and concentratedto give a red oil. Purification by flash chromatography (silica gel, 30%ethyl acetate in hexane) afforded the title compound as a red oil.

[0607]¹H NMR (CDCl₃): δ 1.28 (t, J=7.14 Hz, 3H), 1.34 (3H, s), 1.37 (s,3H), 1.43 (t, J=7.14 Hz, 3H), 1.81 (m, 2H), 2.12 (m, 2H), 2.90 (q,J=7.14 Hz, 2H), 4.22 (q, J=7.14 Hz, 2H), 4.42 (q, J=7.14 Hz, 2H), 7.46(d, J=8.43 Hz, 1H), 7.80 (dd, J=2.07, 6.35 Hz, 1H), 7.91 (d, J=8.55 Hz,2H), 8.17 (d, J=8.55 Hz, 2H), 8.20 (d, J=2.20 Hz, 1H).

[0608] Ethyl4-[(5,5-dimethyl-8(72)-(carbethoxymethylideneyl)-5,6-dihydronaphthalen-2-yl)azo]benzoate(Compound D2a)

[0609] 1Ethyl4-[(5,5-dimethyl-8-(carbethoxymethyl)-5,6-dihydronaphthalen-2-yl)azo]benzoate(Compound D2b)

[0610] A solution of (+/−) ethyl[(5,5-dimethyl-8hydroxy-8-carbethoxymethyl-5,6,7,8-tetrahydronaphth-2-yl)azo]benzoate(Compound D1, 108 mg, 0.25 mmol), DCC (55.9 mg, 0.271 mmol) and CuCl(36.6 mg, 0.37 mmol) in 8 ml of dry benzene was heated under reflux for7 days. After cooling to room temperature, the solids were filtered outand the solution was extracted with ethyl acetate. The combined organiclayer was washed with brine and dried over Na₂SO₄. The solvent wasremoved under reduced pressure, the crude material was purified by flashchromatography (silicagel, 10% ethyl acetate in hexane) to afford thepure title compounds as red oils.

[0611] Ethyl4-[(5,5-dimethyl-8(7H)-(carbethoxymethylidenyl)-5,6-dihydronaphthalen-2-yl)azo]benzoate(Compound D2a)

[0612]¹H NMR (CDCl₃): δ 1.35 (m, 9H), 1.44 (t, J=7.14 Hz, 3H), 1.79 t,J=6.75 Hz, 2H), 3.29 (t, J=6.59 Hz, 2H), 4.27 (q, J=7.14 Hz, 2H), 4.44(q, J=7.14 Hz, 2H), 6.47 (s, 1H), 7.55 (d, J=8.42 Hz, 1H), 7.97 (m, 3H),8.22 (m, 3H).

[0613] Ethyl4-[(5,5-dimethyl-8-(carbethoxymethyl)-5,6-dihydronaphthalen-2-yl)azo]benzoate(Compound D2b)

[0614]¹H NMR (CDCl₃): δ 1.22 (t, J=7.10 Hz, 3H), 1.35 (s, 6H), 1.44 (t,J=7.14 Hz, 3H), 2.32 (d, J=4.39 Hz, 2H), 3.56 (s 2H), 4.17 (q, J=7.14Hz, 2H), 4.44 (q, J=7.14 Hz, 2H), 6.20 (t, J=4.45 Hz, 1H), 7.48 (d,J=8.80 Hz, 1H), 7.81 (m, 2H), 7.92 (d, J=8.49 Hz, 2H), 8.20 (d, J=8.48Hz, 2H).

[0615] Ethyl 4-[(8(2)-anti-(O-methyloxime)-5,5-dimethyl-5,6-dihydronaphthalen-2-yl)azo]benzoate (CompoundD3)

[0616] A solution of ethyl4-[(5,5-dimethyl-5,6-dihydro-naphthalen-8(7H)-one-2-yl)azo]benzoate(Compound D10, 0.13 g, 0.371 mmol) (40 mg, 0.114 mmol), NaOAc (29.3 mg,0.286 mmol) and methoxy amine hydrochloride (14.3 mg, 0.137 mmol) in 3ml of EtOH and 2 ml of THF was stirred at room temperature for twoweeks. The solvent was distilled off and the residue was diluted withethyl acetate. The solution was washed with NaHCO₃ (sat.), water, brineand dried over Na₂SO₄. The solvent was removed under reduced pressure,the residue was purified by flash chromatography to afford the titlecompound as a red solid (34.8 mg).

[0617]¹H NMR (CDCl₃): δ 1.35 (s, 3H), 1.44 (t, J=7.14 Hz, 3H), 1.78 (t,J=6.96 Hz, 2H), 2.83 (t, J=6.90 Hz, 2H), 4.06 (s, 3H), 4.43 (q, J=7.14Hz, 2H), 7.51 (d, J=8.48 Hz, 1H), 7.82 (dd, J=2.20, 6.35 Hz, 1H), 7.96(d, J=8.55 Hz, 2H), 8.21 (d, J=8.48 Hz, 2H), 8.56 (d, J=2.14 Hz, 1H).

[0618] 4-[(8(7H)-Anti-(O-methyloxime)-5,5-dimethyl-5,6-dihydronaphthalen-2-yl)azo]benzoic acid(Compound D4)

[0619] A solution of ethyl 4-[(8(7H)-anti-(O-methyloxime)-5,5-dimethyl-5,6-dihydronaphthalen-2-yl)azo]benzoate (CompoundD3, 57.7 mg, 0.16 mmol) and 2 ml of aqueous NaOH (12%) in 4 ml of THFand 2 ml of EtOH was stirred overnight at room temperature. The reactionwas acidified with 10% HCl (to pH 4 and extracted with EtOAc. Thecombined organic layer was washed with water and brine, and dried overNa₂SO₄. Solvent was removed under reduced pressure ot afford the titlecompound as a red solid.

[0620]¹H NMR (acetone-d₆): δ 1.35 (s, 3H), 1.78 (t, J=6.96 Hz, 2H), 2.82(t, J=6.90 Hz, 2H), 4.00 (s, 3H), 7.67 (d, J=8.54 Hz, 1H), 7.90 (dd,J=2.20, 6.59 Hz, 1H), 8.03 (d, J=8.66 Hz, 2H), 8.24 (d, J=8.48 Hz, 2H),8.54 (d, J=2.14 Hz, 1H).

[0621] (+/−) Ethyl4-[(5,5-dimethyl-8-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)azo]benzoate(Compound D5)

[0622] To a solution of ethyl4-[(5,5-dimethyl-5,6-dihydro-naphthalen-8(7H)-one-2-yl)azo]benzoate(Compound D10, 60 mg, 0.171 mmol) in 2 ml of THF and 7 ml of EtOH at ⁰IC was added NaBH₄ (6.5 mg, 0.171 mmol) and the mixture stirred for 3 h.The reaction was quenched by slow addition of cold water. Solvent wasremoved under reduced pressure and the residue was extracted with ethylacetate. The organic layer was washed with brine, dried (MgSO₄) andsolvent removed under reduced pressure. The crude product was purifiedby flash chromatography (silica, ethyl acetate/hexane, 1: 3) to affordthe title compound as a red oil.

[0623]¹H NMR (CDCl₃): δ 1.31 (s, 3H), 1.38 (s, 3H), 1.43 (t, J=7.14 Hz,3H), 1.68 (m, 1H), 1.92 (m, 2H), 2.13 (m, 1H), 4.42 (q, J=7.14 Hz, 2H),4.85 (m, 1H), 7.49 (d, J=8.48 Hz, 1H), 7.85 (dd, J=2.2, 6.29 Hz, 1H),7.94 (d, J=8.61 Hz, 2H), 8.05 (d, J=2.13 Hz, 1H), 8.20 (d, J=8.55 Hz,2H).

[0624] (+/−) Ethyl4-[(5,5-dimethyl-8-(methoxymethyloxy)-5,6,7,8-tetrahydronaphthalen-2-yl)azo]benzoate(Compound D6)

[0625] To a solution of (+1-) ethyl4-[(5,5-dimethyl-8-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)azo]benzoate(Compound D5, 49.7 mg, 0.141 mmol) in 4 ml of dry CH₂Cl₂ at 0° C. wasadded isopropyl ethyl amine (0.152 ml, 0.847 mmol) followed bychloromethyl methyl ether (0.0323 ml, 0.423 mmol). The reaction mixturewas stirred at room temperature for 12 h. Solvent was removed underreduced pressure, the residue was dissolved in ethyl acetate and thesolution was washed with NaHCO₃ (sat.), and brine. The organic layer wasdried (MgSO₄). The solvent was removed under reduced pressure, theresidue was purfied by flash chromatography (silica, ethylacetate:hexane, 1:3) to afford the title compound as a red oil.

[0626]¹H NMR (CDCl₃): δ 131 (s, 3H), 1.39 (s, 3H), 1.43 (t, J=7.08 Hz,3H), 1.64 (m, 1), 2.07 (m, 3H), 3.52 (s, 3H), 4.43 (q, J=7.08 Hz, 2H),4.75 (t, J=5.06 Hz, 1H), 4.84 (d, J=6.90 Hz, 1H), 4.93 (d, J=6.90 Hz,1H), 7.50 (d, J=8.43 Hz, 1H), 7.83 (dd, J=2.19, 6.29 Hz, 1H), 7.95 (m,3H), 8.19 (d, J=8.55 Hz, 2H).

[0627] (+/−)4-[(5,5-Dimethyl-8-(methoxymethyloxy)-5,6,7,8-tetrahydronaphthalen-2-yl)azo]benzoicacid (Compound D7)

[0628] Using the same procedure as for the preparation of4-[(8(7H)-anti-(O-methyloxime)-5,5-dimethyl-5,6-dihydronaphthalen-2-yl)azo]benzoic acid(Compound D4), (+/−) ethyl4-[(5,5-dimethyl-8-(methoxymethyloxy)-5,6,7,8-tetrahydronaphthalen-2-yl)azo]benzoate(Compound D6, 34 mg, 0.093 mmol) was converted into the title compound(red solid).

[0629]¹H (acetone-d₆): δ 132 (s, 3H), 1.37 (s, 3H), 1.63 (m, 1H), 1.99(m, 3H), 3.45 (s, 3H), 4.75 (t, J=6.1 Hz, 1H), 4.80 (d, J=236.96 Hz,1H), 4.89 (d, J=6.96 Hz, 1H), 7.62 (d, J=8.55 Hz, 1H), 7.84 (dd, J=2.19,6.29 Hz, 1H), 8.00 (m, 3H), 8.22 (d, J=258.55 Hz, 2H).

[0630] 3,4-dihydro-4,4-dimethyl-7-nitro-naphthalen-1 (21-one (CompoundD8)

[0631] To 1.7 mL (3.0 g, 30.6 mmol, 18M) H₂SO₄ at −5_(i)C (ice-NaClbath) was slowly added 783.0 mg (4.49 mmol) of3,4-dihydro-4,4-dimethyl-naphthalen-1(2H)-one. A solution of HNO₃ (426.7mg 6.88 mmol, 0.43 mL, 16M , and 1.31 g (0.013 mol, 0.74 mL, 18 M) ofH₂SO₄ were slowly added. After 20 min, ice was added and the resultingmixture was extracted with EtOAc. The combined extracts wereconcentrated under reduced pressure to give a yellow oil from which thetitle compound, a pale yellow solid, was isolated by columnchromatography (10% EtOAC/hexanes).

[0632]¹H NMR (CDCl₃): δ 8.83 (1H, d, J=2.6 Hz), 8.31 (1H, dd, J=2.8, 8.9Hz), 7.62 (1H, d, J=8.7 Hz), 2.81 (2H, t, J=6.5 Hz), 2.08 (2H, t, J=6.5Hz), 1.45 (6H, s).

[0633] 3,4-dihydro-4,4-dimethyl-7-amino-naphthalen-1(2H)-one (CompoundD9)

[0634] A solution of 230.0 mg (1.05 mmol)3,4-dihydro-4,4-dimethyl-7-nitro-naphthalen-1(2H)-one (Compound D8) in5.0 mL of EtOAc was stirred at room temperature with a catalytic amountof 10% Pd-C under 1 atm of H₂ for 24 h. The catalyst was removed byfiltration through a pad of Celite, and the filtrate concentrated underreduced pressure to give the title compound as a dark green oil.

[0635]¹H NMR (CDCl₃): δ_(—)7.30 (1H, d, J=2.7 Hz), 7.22 (1H, d, J=8.4Hz), 6.88 (1H, dd, J=2.7, 8.5 Hz), 2.70 (2H, t, J=6.6 Hz), 1.97 (2H, t,J=6.6 Hz), 1.34 (6H, s).

[0636] Ethyl4-[(5,6-dihydro-5,5-dimethyl-8(7H)-one-naphthalen-2-yl)azo]-benzoate(Compound D10)

[0637] To a solution of 198.7 mg (1.05 mmol)3,4-dihydro-4,4-dimethyl-7-amino-naphthalen-1(2H)-one (Compound D9) in5.0 mL glacial acetic acid was added 180.0 mg (1.00 mmol) of ethyl4-nitrosobenzoate. The resulting solution was stirred overnight at roomtemperature, and then concentrated under reduced pressure. The productwas isolated from the residual oil as a red solid, by columnchromatography (15% EtOAc-hexanes).

[0638]¹H NMR (CDCl₃): δ 8.57 (1H, d, J=2.0 Hz), 8.19 (2H, d, J=8.4 Hz),8.07 (1H, d, J=8.0 Hz), 7.94 (2H, d, J=8.4 Hz), 7.58 (1H, d, J=8.6 Hz),4.41 (2H, q, J=7.1 Hz), 2.79 (2H, t, J=6.6 Hz), 2.07 (2H, t, J=7.02 Hz),1.44 (6H, s), 1.42 (3H, t, J=7.1 Hz).

[0639] Ethyl4-[(5,6dihydro-5,5-dimethyl-8-(trifluoromethylsulfonyl)oxy-naphthalen-2-yl)azo]-benzoate(Compound D11)

[0640] To a solution of 90.4 mg sodium bis(trimethylsilyl)amide (0.48mmol, 0.48 mL of a 1.0 M THF solution) in 2.0 mL THF at −78_(i)C, wasadded 153.0 mg (0.437 mmol) of ethyl4-[(5,6-dihydro-5,5-dimethyl-8(7H)-one-naphthalen-2-yl)azo]-benzoate(Compound D10) in 2.0 mL THF. The dark red solution was stirred at−78_(i)C for 30 min and then 204.0 mg (0.520 mmol)2-[N,N-bis(trifluoromethylsulfonyl)amino]-5-chloropyridine was added asa solution in 2.0 mL THF. The reaction mixture was allowed to warm toroom temperature and after 3 h was quenched by the addition of H₂O. Theorganic layer was concentrated to a red oil under reduced pressure. Theproduct was isolated by column chromatography (25% EtOAc/hexanes) as ared oil.

[0641]¹H NMR (CDCl₃): d 8.21 (2H, d, J=8.6 Hz), 7.96 (2H, d, J=8.6 Hz),7.94 (2H, m), 7.49 (1H, d, J=8.2 Hz), 6.08 (1H, t, J=0.5 Hz), 4.42 (2H,q, J=7.1 Hz), 2.49 (2H, d, J=4.8 Hz), 1.44 (3H, t, J=7.1 Hz), 1.38 (6H,s).

[0642] Ethyl4-[(5,5-dimethyl-8-(2-thienyl)-5,6-dihydronaphthalen-2-yl)azo]benzoate(Compound D12) 2 To a cold solution (−78° C.) of thiophene (0.07 ml,0.75 mmol) in 1.5 ml of THF was added t-BuLi (0.457 ml, 0.75 mmol, 1.7 Min pentane) and stirred for 2 h. To this solution, ZnCl₂ (168 mg, 1.2mmol) in 1.5 ml of THF was added. The resulting solution was warmed toroom temperature, stirred for 1 h and was added (via cannula) to asolution of ethyl4-[(5,6dihydro-5,5-dimethyl-8-trifluoromethylsulfonyloxy-naphthalen-2-yl)azo]benzoate(Compound D11, 150 mg, 0.30 mmol) andtetrakis(triphenylphosphine)palladium(0) (10.6 mg) in 2.5 ml of THF. Theresulting mixture was heated at 50° C. for 2.5 h. The reaction wasdiluted with sat. aqueous NH₄Cl and extracted with ethyl acetate. Thecombined organic layer was dried over Na₂SO₄ and concentrated to an oil.The crude product was purified by flash chromatography (silica, ethylacetate:hexane 5:95) to afford the title compound as a red foam.

[0643]¹H NMR (CDCl₃): δ 1.40 (s, 6H), 1.44 (t, J=7.14 Hz, 3H), 2.41 (d,J=4.82 Hz, 2H), 4.42 (q, J=7.14 Hz, 2H), 6.29 (t, J=4.83 Hz, 1H), 7.14(m, 2H), 7.32 (dd, J=1.52, 3.36, 1H), 7.53 (d, J=8.31 Hz, 1H), 7.84 (dd,J=2.08, 6.17 Hz, 1H), 7.92 (d, J=8.60 Hz, 2H), 8.03 (d, J=2.07 Hz, 1H),8.18 (d, J=8.61 Hz, 2H).

[0644]4-[(5,5-Dimethyl-8-(2-thienyl)-5,6-dihydronaphthalen-2-yl)azo]benzoicAcid (Compound D13)

[0645] Using the same procedure as for the preparation of4-[(8(7H)-anti-(O-methyloxime)-5,5-dimethyl-5,6-dihydronaphthalen-2-yl)azo]benzoic acid(Compound D4), ethyl4-[(5,5-dimethyl-8-(2-thienyl)-5,6-dihydronaphthalen-2-yl)azo]benzoate(Compound 12, 100 mg, 0.258 mmol) was converted into the title compound(red solid).

[0646]¹H NMR (acetone-d₆): 1.40 (s, 6H, 2.43 (d, J=4.83 Hz, 2H), 2.82(b, 1H), 6.32 (t, J=4.88 Hz, 1H), 7.19 (m, 2H), 750 (d, J=44.88 Hz, 1H),7.65 (d, J=8.24 Hz, 1H), 7.95 (m, 4H), 8.21 (d, J=8.55 Hz, 2H).

[0647] 3,4-dihydro-4,4-dimethyl-7-acetyl-naphthalen-1(2H)-one (CompoundD14a): and 3,4-dihydro-4,4dimethyl-acetyl-naphthalen-1(2H)-one (CompoundD14b)

[0648] To a cold (0° C.) mixture of aluminum chloride (26.3 g, 199.0mmols) in dichloromethane (55 mL) were added acetylchloride (15 g, 192mmols) and 1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (24.4 g, 152mmols) in dichloromethane (20 mL) over 20 minutes. The reaction mixturewas warmed to ambient temparature and stirred for 4 h. Ice (200 g) wasadded to the reaction flask and the mixture diluted with ether (400 mL).The layers were separated and the organic phase was washed with 10% HCl(50 mL), water (50 mL), 10% aqueous sodium bicarbonate, and saturatedaqueous NaCl (50 mL) and thereafter dried over MgSO₄. The solvent wasremoved by distillation to afford a yellow oil which was dissolved inbenzene (50 mL).

[0649] To a cold (0° C.) solution of acetic acid (240 mL) and aceticanhydride (120 mL) was added chromiumtrioxide (50 g, 503 mmols) in smallportions over 20 mins under argon. The mixture was stirred for 30 minsat 0° C. and diluted with benzene (120 mL). The benzene solutionprepared above, was added with stirring via an addition funnel over 20mins. After 8 h, the reaction was quenched by the careful addition ofisopropanol (50 mL) at 0° C., followed by water (100 mL). After 15 mins,the reaction mixture was diluted with ether (1100 mL) and water (200mL), and then neutralized with solid sodium bicarbonate (200 g). Theether layer was washed with water (100 mL), and saturated aqueous NaCl(2×100 mL), and dried over MgSO₄. Removal of the solvent under reducedpressure afforded a mixture of the isomeric diketones which wereseparated by chromatography (5% EtOAc/hexanes).

[0650] (Compound D14a): ¹H NMR (CDCl₃): d 8.55 (1H, d, J=2.0 Hz), 8.13(1H, dd, J=2.0, 8.3 Hz), 7.53 (1H, d, J=8.3 Hz), 2.77 (2H, t, J=6.6 Hz),2.62 (3H, s), 2.05 (2H, t, J=6.6 Hz), 1.41 (6H, s).

[0651] (Compound D14b): ¹H NMR (CDCl₃): d 8.10 (1H, d, J=8.1 Hz), 8.02(1H, d, J=1.6 Hz), 7.82 (1H, dd, J=1.6, 8.1 Hz), 2.77 (2H, t, J=7.1 Hz),2.64 (3H, s), 2.05 (2H, t, J=7.1 Hz), 1.44 (6H, s).

[0652]6-(2-methyl-1,3-dioxolan-2-yl)-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one(Compound D15)

[0653] A solution of 1.80 g (8.34 mmol) of a 1:5 mixture of3,4-dihydro-4,4-dimethyl-7-acetyl-naphthalen-1(2H)-one (Compound D14a);and 3,4-dihydro-4,4-dimethyl-6-acetyl-naphthalen-1(2H)-one (CompoundD14b) in 50 mL benzene was combined with 517.7 mg (8.34 mmol) ofethylene glycol and 20.0 mg (0.11 mmol) of p-toluenesulfonic acidmonohydrate. The resulting solution was heated to reflux for 18 h,cooled to room temperature, and concentrated under reduced pressure. Thetitle compound was isolated by column chromatography (10% EtOAc-hexanes)as a colorless oil.

[0654]¹H NMR (CDCl₃): δ 8.01 (1H, d, J=8.2 Hz), 7.51 (1H, s), 7.43 1(1H,dd, J=1.7, 6.4 Hz), 4.07 (2H, m), 3.79 (2H, m), 2.74 (2H, t, J=6.5 Hz),2.04 (2H, t, J=7.1H), 1.67 (3H, s), 1.46 (6H, s).

[0655] (+/−)6-(2-Methyl-1-1,3-dioxolan-2-yl)]-1,2,3,4-tetrahydro-4,4-dimethyl-1-hydroxy-1-(carboethoxymethyl)-naphthlene(Compound D16)

[0656] Using the same procedure as for the preparation of ethyl4-[(5,6,7,8-tetrahydro-5,5-dimethyl-8-hydroxy-8-(carboethoxymethyl)naphthalen-2-yl)azo]benzoate,6-(2-methyl-1,3-dioxolan-2-yl)]-3,4-dihydro-4,4-dimethylnaphthalen-1(2H-one(Compound D1),6-(2-methyl-1,3-dioxolan-2-yl)-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one(Compound D15, 300 mg, 1.15 mmol) was converted to the title product(321 mg, light yellow oil), using zinc dust (0.5 g, pretreated) andbromo ethyl acetate (0.256 ml, 0.30 mmol) in 10 ml of benzene.

[0657]¹H NMR (CDCl₃): δ 1.29 (t, J=7.08 Hz, 3H), 1.30 (s, 3H), 1.32 (s,3H, 1.65 (s, 3H, 2.06 (s, 2H), 2.80 (q, J=1.45H, 2H), 3.77 (m, 2H), 4.05(m, 2H), 4.13 (q, J=7.14 Hz, 2H), 4.22 (q, J=7.14 Hz, 2H), 7.30 (dd,J=1.71, 6.54 Hz, 1H), 7.42 (d, J=1.77 Hz, 1H), 7.53 (d, J=8.18 Hz, 1H).

[0658]3,4-Dihydro-4,4-dimethyl-1-(carboethoxymethyl)-6acetyl-naphthalene(Compound D17)

[0659] A solution of (+/−)6-(2-methyl-1,3-dioxolan-2-yl)-1,2,3,4-tetrahydro-4,4-dimethyl-1-hydroxy-1-(carboethoxymethyl)-naphthlene((Compound D16, 321 mg, 0.90 mmol) and catalytic amount of TsOH in 20 mlof benzene was refluxed for 12 h. During the reaction the watergenerated from the reaction was periodically removed by a Dean-Starktrap. The solvent was removed and the residue was purified by columnchromatography (silica, ethyl acetate/hexane (1/3)) to give the titlecompound as an oil (215 mg).

[0660]¹H NMR (CDCl₃): δ 1.20 (t, J=7.14 Hz, 3H, 1.33 (s, 6H), 2.30 (d,J=3.42 Hz, 2H), 2.60 (s, 3H), 3.50 (s, 2H), 4.16 (q, J=7.14 Hz, 2H),6.06 (t, J=4.64 Hz, 1H), 7.28 (d, J=2.80 Hz, 1H), 7.76 (, J=1.34, 6.10Hz, 1H), 7.93 (s, 1H). 1

[0661](E)₄-[3-(3.4dihydro-4,4-dimethyl-1-(carboethoxymethyl)-naphthalen-6-yl)-prop-1-en-3-one]benzoicacid (Compound D18)

[0662] To a solution of3,4-dihydro-4,4-dimethyl-1-(carboethoxymethyl)-6-acetyl-naphthalene((Compound D17, 25 mg, 0.10 mmol) and 4-carboxybenzaldehyde (17 mg, 0.13mmol) in 2 ml of MeOH was added aqueous NaOH (0.75 ml, 12%). Thereaction mixture was stirred at room temperature for overnight andquenched by addition of 10% HCl to pH=4.0. The solvent was removed andextracted ethyl acetate, the combined organic layer was washed withwater. The organic layer was dried and concentrated to a white solid.This white solid was dissolved in 1 ml of DMF. To this solution wasadded DMAP (15.2 mg, 0.12 mmol), EDC (22 mg, 0.11 mmol) and 0.5 ml EtOH.The reaction mixture was stirred at room temperature for 5 h andconcentrated in vacuo. The residue was passed through a chromatographiccolumn with ethyl acetate/hexane (1/9) to give the title compound as alight tan solid.

[0663]¹H NMR (CDCl₃): δ 1.21 (t, J=7.14 Hz, 3H), 1.36 (s, 6H), 1.42 (t,J=7.14 Hz, 3H), 2.33 (d, J=4.46 Hz, 2H), 4.13 (q, J=7.14 Hz, 2H), 4.41(q, J=7.14H, 2H), 6.09 (t, J=4.79 Hz, 1H), 7.32 (d, J=8.05 Hz, 1H), 7.60(d, J=15.6 Hz, 1H), 7.70 (d, J=8.36 Hz, 2H), 7.80 (s, 1H), 7.85 (d,J=8.12 Hz, 1H), 8.00 (d, J=1.77 Hz, 1H), 8.10 (d, J=8.36 Hz, 2H).

[0664]3,4-Dihydro-4,4-dimethyl-6-acetyl-1-(1,1-dimethylethyl)naphthalene(Compound D19)

[0665] To a solution of6-(2-methyl-1,3-dioxolan-2-yl)]-3,4-dihydro-4,4-dimethylnaphthlen-1(2H)-one((Compound D1S, 353 mg, 1.36 mmol) in 3 ml of dry ether at −78° C. wasadded dropwise t-BuLi (1 ml, 1.7 mmol, 1.7 M solution in pentane). Thisclear light yellow solution was left at −78° C. for 30 min. Then,freshly distilled SOCl₂ (0.15 ml, 2.0 mmol) was added. The reactionmixture was stirred at −78° C. for additional 30 min and thereafterslowly warmed to room temperature. The reaction was quenched by additionof saturated NH₄Cl. The white solids were removed by filtration and theclear solution was concentrated to an oil, and purified by columnchromatography with ethyl acetate/hexane (1/10) to give the titlecompound as a yellow oil.

[0666]¹H NMR (CDCl₃): U 7.92 (d, J=1.79 Hz, 1H), 7.76 (dd, J=1.80, 8.23Hz, 1H), 7.73 (d, J=8.23 Hz, 1H), 6.10 (t, J=4.98 Hz, 1H), 2.58 (s, 3H),2.18 (d, J=5.00 Hz, 2H), 1.34 (s, 9H), 1.25 (s, 6H).

[0667](E)-4-[3-(3,4-Dihydro-4,4-dimethyl-1-(1,1-dimethyl-ethyl)naphth-6-yl)-prop-1-en-3-one]benzoicacid (Compound D20)

[0668] To a solution of3,4-dihydro-4,4-dimethyl-6-acetyl-1-(1,1-dimethylethyl)naphthalene(Compound D19, 60 mg, 0.234 mmol) and 4-carboxybenzaldehyde (35 mg,0.233 mmol) in 5 ml of EtOH and 1 ml of THF was added 3 ml of 1 Maqueous NaOH. The yellow reaction mixture was left overnight when itturned red and then quenched with 6% HCl until it became yellow again.The solvent was removed and the residue was dissolved in ethyl acetate.The organic solution was washed with brine and dried. After evaporationof the solvent, the residue was purified by recrystallization from ethylacetate to give 28 mg title compound as yellow crystals.

[0669]¹H NMR (CDCl₃): δ 8.15 (d, J=8.31 Hz, 2H), 8.00 (d, J=1.80 Hz,1H), 7.86 (dd, J=1.83, 8.24H, 1H), 7.83 (d, J=15.82 Hz, 1H), 7.78 (d,J=8.48 Hz, 1H), 7.74 (d, J=8.31 Hz, 2H), 7.65 (d, J=15.87 Hz, 1H), 6.13(t, J=5.0 Hz, 1H), 2.21 (d, J=4.9 Hz, 2H), 1.38 (s, 9H), 1.30 (s, 6H).

[0670] 6-Bromo-1(2H)-(propyliden-2-yl)-3,4-dihydro-4,4-dimethylnaphthalene (CompoundD21)

[0671] To a mixture of TiCl₃ (5 g, 32 mmol) of in 80 ml of dry DME underargon atmosphere was added in small portions lithium wire (0.80 g, 92mmol). The reaction mixture was heated at 85° C. for 1 h and then cooledto room temperature. To the above solution was added a mixture of6-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound H, 1.00g, 4.0 mmol) in 10 ml of dry DME and 10 ml of dry acetone through acannula. The resulting mixture was heated to reflux and was left for 12h and then cooled to room temperature. The reaction mixture was dilutedwith 80 ml of hexane and then filtered through florisil. Purification bycolumn chromatography with pure hexane as the eluent gave the titlecompound as a clear oil.

[0672]¹H NMR (CDCl₃): δ 1.23 (s, 6H), 1.60 t, J=7.09 Hz, 2H), 1.82 (s,3H), 1.92 (s, 3H), 2.49 (t, J=6.60 Hz, 2H), 7.10 (d, J=8.30 Hz, 1H),7.26 (dd, J=1.95, 6.05 Hz, 1H), 7.40 (d, J=2.08 Hz, 1H).

[0673]6-Acetyl-1(2H)-(propyliden-2-yl)-3.4dihydro-4,4-dimethylnaphthalene(Compound D22)

[0674] To a solution of 6bromo-1(2H)-(propyliden-2-yl)-3,4dihydro-4,4-dimethylnaphthalene (Compound D21, 910 mg, 3.3 mmol) andbis(triphenylphosphine)palladium(II) chloride (100 mg, 0.14 mmol) of in50 ml of DMF under argon was added (1-ethoxyvinyl)tributyl tin (1.713ml, 5.07 mmol). The resulting reaction mixture was heated at 85° C. for48 h and cooled down to room temperature. The reaction was quenched with15 ml of 10% HCl and then diluted with ethyl acetate. The organic layerwas washed with brine and dried over MgSO₄. Purification by columnchromatography with pure hexane afforded the title compound as a yellowoil (410 mg).

[0675]¹H NMR (CDCl₃): δ 1.28 (s, 6H), 1.64 (t, J=6.99 Hz, 2H), 1.86 (s,3H), 1.97 (s, 3H), 2.53 (t, J=6.6 Hz, 2H), 2.61 (s, 3H), 7.31 (d, J=8.06Hz, 1H), 7.74 (dd, J=1.96, 6.10 Hz, 1H), 7.92 (d, J=1.89 Hz, 1H).

[0676](E)-4-[3-{1(2H)-(propyliden-2-yl)-3,4-dihydro-4,4-dimethylnaphthalen-6-yl}-prop-1-en-3-one]benzoicAcid (Compound D23)

[0677] The title compound can be obtained by following the procedureemployed for the preparation of(E)-4-[3-(3,4-dihydro-4,4-dimethyl-1-(carboethoxymethyl)-naphthalen-6-yl)-prop-1-en-3-one]benzoicacid (Compound D18).

[0678] (+/−)1-Hydroxy-6-(1,3-dioxolan-2-yl)]-1,2,3,4-tetrahydro-4,4-dimethylnaphthalene(Compound D24)

[0679] To a solution of6-(1,3-dioxolan-2-yl)]-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one(Compound D15, 110 mg, 0.42 mmol) in 6 ml of EtOH at 0° C. was addedNaBH₄ (16 mg, 0.42 mmol). The reaction mixture was stirred for 4 h andkept in a freezer for overnight. The reaction was quenched with slowaddition of cold water and extracted with ethyl acetate. The organiclayer was dried and concentrated to an oil. Purification by columnchromatography with ethyl acetate/hexane (13) gave the title compound asa clear oil.

[0680]¹H NMR (CDCl₃): δ 1.26 (s, 3H), 1.34 (s, 3H), 1.65 (s, 3H), 1.61(m, 1H), 1.89 (m, 2H), 2.07 (m, 1H), 3.74 (m, 2H), 4.05 (m, 2H), 4.74(t, J=5.10 Hz, 1H), 7.30 (dd, T=1.65, 6.16, 1H), 7.41 (d, J=7.94 Hz,1H), 7.45 (d, J=1.83 Hz, 1H).

[0681] (+/−)1-Hydroxy-6-acetyl-1,2,3,4tetrahydro-4,4-dimethyl-naphthalene (CompoundD25),

[0682] A solution of1-hydroxy-6-(1,3-dioxolan-2-yl)]-1,2,3,4-tetrahydro-4,4-dimethylnaphthalene(Compound D24, 54.9 mg, 0.21 mmol) in 3 ml of 10% HCl and 3 ml THF washeated at 100° C. for 1.5 h and cooled to room temperature. The reactionmixture was diluted with ethyl acetate and neutralized with sat. NaHCO₃.The organic layer was further washed with brine, dried and concentratedto an oil. Purification by column chromatography (silica) with ethylacetate/hexane (1/9) gave the title compound as a clear oil (24.8 mg).

[0683]¹H NMR (CDCl₃): δ 1.29 (s, 3H), 1.34 (s, 3H), 1.66 (m, 1H), 1.89(m, 2H), 2.10 (m, 1H), 2.56 (s, 3H), 4.75 (t, J=4.90, 1H), 7.54 (d,J=8.18 Hz, 1H), 7.75 (dd, J=1.83, 6.29 Hz, 1H), 7.94 (d, J=1.77 Hz, 1H).

[0684] (+1-)1-(Methoxymethyloxy)-6-acetyl-1,2,3,4-tetrahydro-4,4-dimethyl-naphthalene(Compound D26)

[0685] A solution of (+/−)1-hydroxy-6-acetyl-1,2,3,4-tetrahydro-4,4-dimethyl-naphthalene (CompoundD25, 24.8 mg, 0.11 mmol), chloromethyl methyl ether (0.12 mmol),triethyl amine (0.02 ml, 0.13 mmol) and catalytic amount oftetrabutylammonium bromide in 2 ml of CH₂Cl₂ was stirred at roomtemperature for 5 h. Purification by column chromatography (silica) withethyl acetate/hexane (1/10) afforded the title compound as an oil (17.8mg).

[0686]¹H NMR (CDCl₃): δ 7.95 (d, J=1.7 Hz, 1H), 7.73 (dd, J=1.7, 8.4 Hz,1H), 7.44 (d, J=8.4 Hz, 1H), 4.88 (d, J=6.41 Hz, 1H), 4.76 (d, J=6.41Hz, 1H), 4.67 (m, 1H), 3.48 (s, 3H), 2.59 (s, 3H), 2.00 (m, 3H), 1.58(m, 1H), 1.37 (s, 3H), 1.29 (s, 3H).

[0687](E)-4-[3-(1,2,3,4-Tetrahydro-4,4-dimethyl-1-(methoxymethyloxy)-naphthalen-6-yl)-prop-1-en-3-one]benzoicacid (Compound D27)

[0688] The title compound can be prepared by following the procedureemployed for the preparation of(E)-4-[3-(3,4-dihydro-4,4-dimethyl-1-(carboethoxymethyl)-naphthalen-6-yl)-prop-1-en-3-one]benzoic,acid (Compound D18).

[0689] 6-Acetyl-1 (2H)—(O-methyloxime)-3,4-dihydro-4,4-dimethylnaphthalene (Compound D28)

[0690] To a solution of6-(1,3-dioxolan-2-yl)]-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one(Compound D15, 100 mg, 0.38 mmol), NaOAc (78.8 mg, 0.95 mmol) in 5 ml ofEtOH and 2 ml of THF was added methoxyamine hydrochloride (32.1 mg, 0.38mmol). The resulting mixture was stirred at room temperature forovernight. The solvent was removed and the residue was dissolved inethyl acetate (5 mL) and washed with saturated NaHCO₃, water and brine.The solvent was distilled off and the crude product was purified bycolumn chromatography with ethyl acetate/hexane (1/3) to give the titlecompound as an oil.

[0691]¹H NMR (CDCl₃): δ 1.42 (s, 6H), 2.03 (t, J=6.07 Hz, 2H), 0.2.24(s, 3H), 2.74 (t, J=6.71 Hz, 2H), 4.04 (s, 3H), 7.56 (dd, J=1.52, 6.72Hz, 1H), 7.70 (d, J=1.75 Hz, 1H), 8.02 (d, J=8.24 Hz, 1H).

[0692] (E)-4-[3-{1(2H)—(O-methyloxime)-3,4-dihydro-4,4-dimethylnaphthalen-6-yl}-prop-1-en-3-one]benzoicAcid (Compound D29)

[0693] The title compound can be prepared by following the procedureemployed for the preparation of(E)-4-[3-(3,4-dihydro-4,4-dimethyl-1-(carboethoxymethyl)-naphthalen-6-yl)-prop-1-en-3-one]benzoicacid (Compound D18).

[0694]3,4-dihydro-1-(trifluoromethylsulfonyl)ox-4,4-dimethyl-6-(2-(2-methyl-1,3-dioxolanyl))naphthalene(Compound D30)

[0695] To a cold solution (−78° C.) of 232.7 mg (1.267 mmol) of sodiumbis(trimethylsilyl)amide in 2.0 ml of THF was added a solution of 300.0mg (1.154 mmol) of6-(1,3-dioxolan-2-yl)]-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one(Compound D15) in 4.0 ml of THF. The reaction mixture was stirred at−78° C. for 30 minutes and then a solution of 498.0 mg (1.269 mmol) of5-chloro(2-bis-triflouromethylsulfonyl)imide in 3.0 ml of THF was added.After stirring at −78° C. for 1 hour, the solution was warmed to 0° C.and stirred for 12 hours. The reaction was quenched by the addition ofsaturated aqueous NH₄Cl. The mixture was extracted with EtOAc (50 ml)and the combined organic layers were washed with saturated aqueousNaHCO₃, water, and brine. The organic phase was dried over Na₂SO₄ andthen concentrated in vacuo to a yellow oil. Purification by columnchromatography (silica, 10% EtOAc-hexanes) yielded the title compound asa clear yellow oil.

[0696]¹H NMR (CDCl₃): , 7.43 (1H, s), 7.38 (2H, m), 5.95 (1H, t, J=4.8Hz), 4.07 (2H, m) 3.77 (2H, m) 2.42 (2H, d, J=4.9 Hz), 1.66 (3H, s),1.32 (6H, s).

[0697]3,4-dihydro-1-(2-thienyl)-4,4-dimethyl-6-(2-(2-methyl-1,3-dioxolanyl))naphthalene(Compound D32)

[0698] A solution of 2-thienyllithium was prepared by the addition of106.9 mg (0.67 ml, 1.67 mmol) of n-butyl lithium (2.5 M solution in′hexanes) to a cold solution (00 C) of 140.0 mg (1.67 mmol) of thiophenein 1.0 ml of THF. After stirring for 3 h a solution of 364.0 mg (2.67mmol) of zinc chloride in 2.0 ml of THF was added. The resultingsolution was warmed to room temperature, stirred for 30 minutes, andadded via cannula to a solution of 262.0 mg (0.668 mmol) of3,4-dihydro-1-(trifluoromethylsulfonyl)oxy-4,4-dimethyl-6-(2-(2-methyl-1,3-dioxolanyl))naphthalene(Compound D30) and 30 mg (0.03 mmol) oftetrakis(triphenylphosphine)palladium(0) in 2.0 ml of THF. The resultingsolution was heated at 500 C for 12 h, cooled to room temperature anddiluted with saturated aqueous NH₄Cl. The mixture was extracted withEtOAc and the combined organic layers were washed with water and brine.The organic phase was dried over Na₂SO₄ and concentrated in vacuo to ayellow oil. Purification by column chromatography (10% EtOAc-hexanes)yielded the title compound as a yellow solid.

[0699]¹H NMR (CDCl₃): δ 7.48 (1H, d, J=1.8 Hz), 7.34 (1H, d, J=7.9 Hz),7.28 (2H, m), 7.08 (2H, m), 6.18 (1H, t, J=4.8 Hz), 4.06 (2H, m), 3.82(2H, m), 2.34 (2H, d, J=4.8 Hz), 1.70 (3H, s), 1.34 (6H, s).

[0700] 3,4-dihydro-1-(2-thienyl)-4,4-dimethyl-6-acetylnaphthalene(Compound D33)

[0701] A solution of3,4-dihydro-1-(2-thienyl)4,4-dimethyl-6-(2-(2-methyl-1,3-dioxolanyl))naphthalene(Compound D32, 103.0 mg, 0.32 mmol) in 4.0 mL THF and 4.0 mL 10% aqueousHCl was refluxed for 1.5 h. Upon cooling to room temperature, thereaction mixture was diluted with EtOAc and washed with water andsaturated aqueous NaCl. The organic layer was dried over MgSO₄ and thesolvents were removed under reduced pressure to give the title compoundas a colorless oil after column chromatography (10% EtOAc-hexanes).

[0702]¹H NMR (CDCl₃): δ 7.98 (1H, d, J=1.8 Hz), 7.75 (1H, dd, J=1.8, 8.1Hz), 7.46 (1H, d, J=38.1 Hz), 7.29 (1H, d, J=5.0 Hz), 7.09 (2H, m), 6.32(1H, t, J=4.8 Hz), 2.61 (3H, s), 2.38 (2H, d, J=4.9 Hz), 1.38 (6H, s).

[0703]4-[3-oxo-3-(7,8-dihydro-5-(2-thienyl)-8,8-dimethyl-2-naphthalenyl)-1-propenyl]-benzoicAcid (Compound D34)

[0704] To a solution of 62.6-mg (0.222 mmol)3,4-dihydro-1-(2-thienyl)-4,4-dimethyl-6-acetylnaphthalene (CompoundD33) in 4.0 mL of MeOH were added 33.4 mg (0.222 mmol) of 4-carboxybenzaldehyde, and 240.0 mg (6.00 mmol; 2.0 mL of 3M aqueous NaOH). Theresulting solution was stirred at room temperature for 12 h,concentrated under reduced pressure, and the residual oil dissolved inEtOAc. The solution was treated with 10% HCl, and the organic layerwashed with H₂O, and saturated aqueous NaCl, before being dried overNa₂SO₄. Removal of the solvents under reduced pressure gave the titlecompound as a pale green solid after recrystallization from EtOH.

[0705]¹H NMR (acetone-d₆): δ 8.16 (1F s), 8.10 (1H, d, J=8.4 Hz), 8.00(5H, m), 7.84 (1H, d, J=15.5 Hz), 7.48 (2H, m), 7.14 (2H, m), 6.36 (1H,t, J=4.8 Hz), 2.83 (1H, s), 2.43 (2H, d, J=4.8 Hz), 1.39 (6H, s).

[0706] Methyl-5,5-dimethyl-5,6dihydro-naphthalen-8(2H)-one-2-carboxylate(Compound E2)

[0707] A degassed (with carbonmonoxide) solution of2-bromo-5,5-dimethyl-5,6-dihydro-naphthalen-8(7H)-one (Compound G),palladium(II)-bis(triphenylphosphine)chloride (277 mg, 0.4 mmol),1,3-bis(diphenylphosphino)-propane (325 mg, 0.8 mmol), DMSO (30 mL),methanol (15 mL) and triethylamine (15 mL) was placed in an oil bath(70° C.), under carbonmonoxide atmosphere) for 16 h. After dilution withwater the mixture was extracted with ethyl acetate. The organic layerwas washed with water, 10% HCl, saturated sodiumbicarbonate and brine.The organic layer was dried over MgSO₄, and the solvent was removed bydistillation. The residual crude material was purified by flashchromatography (silica, 1:4 ethyl acetate:hexane ) to afford the titlecompound as a white solid.

[0708]¹HNMR (CDCl₃): δ 1.42 (s, 6H), 2.05 (t, J=6.6 Hz, 2H), 2.77 (dd,J=6.6, 2H), 3.93 (s, 3H), 7.52 (d, J=8.3 Hz, 1H), 8.17 (dd, J=1.8, 8.3Hz, 1H), 8.67 (d, J=1.8 Hz, 1H).

[0709] 5,5-Dimethyl-5,6-dihydro-naphthalen-8(2)-one-2-carboxylic Acid(Compound E3)

[0710] To a solution ofmethyl-5,5-dimethyl-5,6-dihydro-naphthalen-8(7H)-one-2-carboxylate(Compound E2, 1.05 g, 4.5 mmol) in 10 mL of ethanol and THF (10 mL) wasadded sodiumhydroxide 9 mL (1M solution). The solution was stirred for16 h and thereafter acidified with 10% HCl. The mixture was extractedwith ethyl acetate, the combined organic layer was washed with water andbrine, and dried over MgSO4. The solvent was distilled off under reducedpressure to afford the title compound as a white solid.

[0711]¹HNMR (Acetone-D6): δ 1.44 (s, 6H), 2.07 (t, J=6.7 Hz, 2H), 2.73(t, J=6.7 Hz, 2H), 7.70 (d, J=8.2 Hz, 1H), 8.19 (dd, J=1.9, 8.2 Hz, 1H),8.57 (d, J=1.9 Hz, 1H).

[0712] Methyl5,5-dimethyl-5,6-dihydro-8-(trifluoromethylsulfonyl)oxy-naphthalene-2-carboxylate(Compound E4)

[0713] To a solution of sodium bis(trimethylsilyl)amide (550.1 mg, 3.00mmol, 3.0 mL of a 1.0 M solution in THF) in 5.0 mL of THF at −78° C. wasadded 620.0 mg (2.67 mmol) ofmethyl-5,5-dimethyl-5,6-dihydro-naphthalen-8(7H)-one-2-carboxylate(Compound E2) in 8.0 mL of THF. After 30 min a solution of 1.15 g (2.94mmol) of 2-N,N-bis(trifluoromethylsulfonyl)amino-5-chloropyridine in 6.0mL of THF was added. Stirring for 45 min at −78° C. was followed bywarming to room-temperature and stirring for 5 h. The reaction wasquenched by the addition of saturated aqueous NH₄Cl and extracted withEtOAc. The combined organic layers were washed with 5% aqueous NaOH anddried over MgSO₄. Concentration of the dry solution under reducedpressure to an oil and column chromatography using 10% EtOAc-hexanesafforded the title compound as a yellow oil.

[0714]¹H NMR(CDCl₃) δ 1.33 (s, 6H), 2.45 (d, J=4.8 Hz, 2H), 3.93 (s,3H), 6.03 (t, J=4.8 Hz, 1H), 7.40 (d, J=8.5 Hz, 1H), 8.00 (m, 2H).

[0715] Methyl5,5-dimethyl-5,6-dihydro-8-(2-thienyl)-naphthalene-2-carboxylate(Compound E5)

[0716] To a solution of 329.0 mg (3.93 mmol) of thiophene in 2.0 mL THFat 0° C. was added 251.8 mg (3.93 mmol, 1.56 mL of 2.5 M solution inhexanes) of n-butyllithium. After stirring for 3 h at 0° C., a solutionof 845.0 mg (6.28 mmol) of ZnCl₂ in 5.0 mL THF was added and theresulting solution stirred for 30 minutes. This solution was added to asecond flask containing 570.0 mg (1.57 mmol) of methyl5,5-dimethyl-5,6-dihydro-8-(trifluoromethylsulfonyl)oxy-naphthalene-2-carboxylate(Compound E4) and 76.0 mg (0.063 mmol) oftetrakis(triphenyphosphine)palladium(0) in 4.0 mL THF, and the resultingsolution was heated to 50° C. for 3 h. Upon cooling to room temperaturethe reaction was quenched by the addition of saturated aqueous NH₄Cl.Extraction with EtOAc was followed by washing of the combined organiclayers with H₂O and saturated aqueous NaCl, and drying over MgSO₄. Thedry solution was concentrated under reduced pressure and the titlecompound was isolated from the residue as a yellow oil by columnchromatography (5-10% EtOAc/hexanes).

[0717]¹H NMR(CDCl₃): δ 1.34 (s, 6H), 2.35 (d, J=4.9 Hz, 2H), 3.86 (s,3H), 6.23 (t, J=4.9 Hz, 1H), 7.06 (m, 2H), 7.28 (m, 1H), 7.43 (d, J=8.0Hz, 1H), 7.92 (dd, J=1.7, 8.0 Hz, 1H), 8.06 (d, J=1.7 Hz, 1H).

[0718] 5,5-dimethyl-5,6-dihydro-8-(2-thienyl)-naphthalene-2-carboxylicAcid (Compound E6)

[0719] To a solution of methyl5,5-dimethyl-5,6-dihydro-8-(2-thienyl)-2-naphthalenecarboxylate(Compound E5, 430.0 mg, 1.44 mmol) in 3.0 mL of EtOH and 3.0 mL THF wasadded NaOH (240.0 mg, 6.00 mmol; 3.0 mL of a 2N aqueous solution). Theresulting solution was warmed to 35° C. for 6 h, cooled to roomtemperature and quenched with 1M HCl. The mixture was extracted withEtOAc and the combined organic layers washed with H₂O and saturatedaqueous NaCl before being dried over MgSO₄. Removal of the solventsunder reduced pressure afforded the title compound as a pale yellowsolid.

[0720]¹H NMR(CDCl₃) Î 1.34 (s, 6H, 2.38 (d, J=4.8 Hz, 2H), 6.25 t, J=4.8Hz, 1H), 7.12 (m. 3H), 7.45 (dd, J=1.8, 4.7 Hz, 1H), 7.54 (d, J=8.0 Hz,1H), 7.92 (dd, J=1.8, 8.0 Hz, 1H), 8.06 (d, J=1.8 Hz, 1H).

[0721] Ethyl4-[[(5,5-dimethyl-5,6-dihydro-8-(2-thienyl)-naphthalen-2-yl)carboxamido]-benzoate(Compound E7)

[0722] A solution of5,5-dimethyl-5,6-dihydro-8-(2-thienyl)-naphthalene-2-carboxylic acid(Compound E6, 180.0 mg, 0.638 mmol), ethyl 4-aminobenzoate (137.0 mg,0.829 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(160.0 mg, 0.829 mmol), and 4-N,N-dimethylaminopyridine (101.0 mg, 0.829mmol) in 6.0 mL DMF was stirred overnight at room temperature. EtOAc(100 mL) was added and the solution washed with H₂O, 5% HCl, saturatedaqueous NaHCO₃, and saturated aqueous NaCl before being dried overMgSO₄. Removal of the sovents under reduced pressure and columnchromatography (10-25% EtOAc-hexanes) of the residual oil afforded thetitle compound as a colorless solid.

[0723]¹H NMR(CDCl₃): δ 1.36 (s, 6H), 1.39 (t, J=7.1 Hz, 3H), 2.38 (d,J=4.8 Hz, 2H), 4.36 (q, J=7.1 Hz, 2H), 6.27 (t, J=4.8 Hz, 1H), 7.09 (m,2H), 7.29 (m, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.68 (d, J=8.8 Hz, 2H), 7.76(dd, J=1.9, 8.0 Hz, 1H, 7.83 (S, 1H), 7.88 (d, J=1.9 Hz, 1H), 8.03 (d,J=8.8 Hz, 2H).

[0724]4-[[(5,5-Dimethyl-5,6-dihydro-8-(2-thienyl)-naphthalen-2-yl)carboxamido]-benzoicAcid (Compound E8)

[0725] To a solution of ethyl4-[[(5,5-dimethyl-5,6-dihydro-8-(2-thienyl)-naphthalen-2-yl)carboxamido]-benzoate(Compound E7, 110.0 mg, 0.255 mmol) in 2.0 mL of EtOH and 1.0 mL THF wasadded NaOH (80.0 mg, 2.00 mmol; 2.0 mL of a 1N aqueous solution). Afterstirring overnight at room temperature the reaction was quenched by theaddition of 1M aqueous HCl. The mixture was extracted with EtOAc and thecombined organic layers washed with H₂O and saturated aqueous NaClbefore being dried over MgSO₄. Removal of the solvents under pressureafforded the title compound as a pale yellow solid.

[0726]¹H NMR(acetone-d₆): δ 1.34 (s, 6H), 2.38 (d, J=4.9 Hz, 2H), 6.27(t, J=4.9 Hz, 1H), 7.12 (m, 2H), 7.44 (dd, J=1.3, 5.0 Hz, 1H), 7.55 (d,J=8.0 Hz, 1H), 7.88 (m. 3H), 8.02-7.91 (m, 3H), 9.75 (s, 11H).

[0727] Ethyl4-[[(5,5-dimethyl-5,6-dihydro-8-(2-thienyl)-naphthalen-2-yl)carbonyl]oxy]-benzoate(Compound E9)

[0728] A solution of5,5-dimethyl-5,6-dihydro-8-(2-thienyl)-naphthalene-2-carboxylic acid(Compound E6, 50.0 mg, 0.177 mmol), ethyl 4-hydroxybenzoate (38.2 mg,0.230 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(44.0 mg, 0.230 mmol), and 4-N,N-dimethylaminopyridine (28.0 mg, 0.230mmol) in 2.0 mL DMF was stirred overnight at room temperature. EtOAc (50mL) was added and the solution washed with H₂O, 5% HC, saturated aqueousNaCO₃, and saturated aqueous NaCl before being dried over MgSO₄. Removalof the sovents under reduced pressure and column chromatography (10%EtOAc-hexanes) of the residual oil afforded the title compound as a acolorless solid.

[0729]¹H NMR(CDCl₃): δ 1.36 (s, 6H), 1.39 (t, J=7.2 Hz, 3H), 2.39 (d,J=4.9 Hz, 2H), 4.38 (q, J=7.2 , 2H), 6.26 (t, J=4.9 Hz, 1H), 7.09 (m,2H), 7.25 (m, 2H), 7.49 (d, J=8.2 Hz, 1H), 8.08 (m, 3H), 8.22(d, J=1.8Hz, 1H).

[0730] 2-trimethylsilylethyl4-[[(5,5-dimethyl-5,6-dihydro-8-(2-thienyl-naphthalen-2-yl)carbonyl]oxy]-benzoate(Compound E10)

[0731] A solution of5,5-dimethyl-5,6-dihydro-8-(2-thienyl)-naphthalene-2-carboxylic acid(Compound E6, 79.0 mg, 0.280 mmol), 2-trimethylsilylethyl4-hydroxybenzoate (73.3 mg, 0.308 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (70.0 mg,0.364 mmol), and 4-N,N-dimethylaminopyridine (44.5 mg, 0.364 mmol) in2.0 mL DMF was stirred overnight at room temperature. Et₂O (100 mL) wasadded and the solution washed with H₂O; 5% HCl, saturated aqueous NaCO₃,and saturated aqueous NaCl before being dried over MgSO₄. Removal of thesovents under reduced pressure and column chromatography (10%EtOAc-hexanes) of the residual oil afforded the title compound as acolorless solid.

[0732]¹H NMR(CDCl₃): δ 0.10 (s, 9H), 1.15 (t, J=8.2 Hz, 2H), 1.38 (s,61), 2.39 (d, J=4.0 Hz, 2H), 4.43 (t, J=8.2 Hz, 2H, 6.28 (t, J=4.0 Hz,1H), 7.09 (m, 2H), 7.26 (m, 3H), 7.52 (d, J=7.2 Hz, 1H), 8.09 (m, 3H),8.22 (s, 1H).

[0733]4-[[(5,5-Dimethyl-5,6-dihydro-8-(2-thienyl)-naphthalen-2-yl)carbonyl]oxy]-benzoicAcid (Compound E11)

[0734] To a solution of 2-trimethylsilylethyl4-[[(5,5-dimethyl-5,6-dihydro-8-(2-thienyl)-naphthalen-2-yl)carbonyl]oxy]-benzoate(Compound E10, 100.0 mg, 0.198 mmol) in 2.0 mL THF at room temperaturewas added 155.3 mg of tetrabutylammonium fluoride (0.594 mmol 0.6 mL ofa 1M solution in THF). After stirring overnight the reaction was dilutedwith EtOAc and washed with H₂O and saturated aqueous NaCl before beingdried over MgSO₄. The solvents were removed under reduced pressure andthe residue washed with hot acetonitrile leaving the product as acolorless solid.

[0735]¹H NMR(acetone-d₆): δ 1.37 (s, 6H), 2.42 (d, J=4.8 Hz, 2H), 6.30(t, J=4.8 Hz, 1H), 7.14 (m, 2H), 7.37 (d, J=8.6 Hz, 2H), 7.44 (dd,J=1.1, 5.0 Hz, 1H), 7.65 (d, J=8.1 Hz, 1H), 8.12 (m, 4H).

[0736]1(2H)-(Propyliden-2-yl)-3,4-dihydro-4,4-dimethylnaphthalene-7-carboxylicAcid (Compound E12)

[0737] To a cold (−78° C.) solution of7-bromo-1(2H)-(propyliden-2-yl)-3,4-dihydro-4,4-dimethylnaphthalene(Compound A37, 640.0 mg, 2.30 mmol) in 20 mL THF was addedt-butyllithium (294.7 mg, 4.60 mmol; 2.7 mL of a 1.7M solution inpentane). After 1 h dry CO₂ gas was bubbled through the solution for 1h. The resulting mixture was allowed to warm to room temperature andthen quenched with 10% aqueous HCl. The mixture was extracted with EtOAcand the combined organic layers washed with H₂O and saturated aqueousNaCl before being dried over Na₂SO₄. Concentration of the dry solutionunder reduced pressure and washing of the residue with hexanes affordedthe title compound as a pale yellow solid.

[0738]¹H NMR(acetone-d₆): δ 1.25 (s, 6H), 1.63 (t, J=6.9 Hz, 2H), 1.85(s, 3H), 1.95 (s, 3H), 2.53 (t, J=6.9 Hz, 2H), 7.43 (d, J=8.1 Hz, 1H),7.82 (dd, J=1.8, 8.1 Hz, 1H), 7.94 (d, 1.8H, 1H).

[0739]2-(trimethylsilyl)ethyl-4-[{(5,5-dimethyl-8(72-(propyliden-2-yl)-5,6-dihydronaphthalen-2-yl)}carbonyl}oxy]benzoate(Compound E13)

[0740] A solution of5,5-dimethyl-5,6-dihydro-8(7H)-(1-propyliden-2-yl)-naphthalene-2-carboxylicacid (Compound E12, 70.0 mg, 0.287 mmol), 2-trimethylsilylethyl4-hydroxybenzoate (71.0 mg, 0.298 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (71.0 mg,0.370 mmol), and 4-N,N-dimethylaminopyridine (45.0 mg, 0.370 mmol) in2.0 mL DMF was stirred overnight at room temperature. Et₂O (100 mL) wasadded and the solution washed with H₂O, 5% HCl, saturated aqueousNaHCO₃, and saturated aqueous NaCl before being dried over MgSO₄.Removal of the solvents under reduced pressure and column chromatography(5% EtOAc-hexanes) of the residual oil afforded the title compound as acolorless oil.

[0741]¹H NMR(CDCl₃): δ 0.09 (s, 9H), 1.14 (t, J=8.4 Hz, 2H), 1.28 (s,6H), 1.66 (d, J=6.9 Hz, 2H), 1.86 (s, 3H), 2.00 (s, 3H), 2.54 (t, J=6.9Hz, 2H), 4.30 (t, J=8.4 Hz, 2H), 7.28 (d, J=8.7 Hz, 2H), 7.43 (d, J=8.1Hz, 1H), 7.97 (dd, J=1.9, 8.1 Hz, 1H), 8.08 (d, J=1.9 Hz, 1H), 8.11 (d,J=8.7 Hz, 2H).4-[((5,5-Dimethyl-8(72)-(propyliden-2-yl)-5,6-dihydronaphthalen-2-yl)}carbonyl}oxy]benzoicAcid (Compound E14)

[0742] To a solution of 2-trimethylsilylethyl4-[[(5,5-dimethyl-5,6-dihydro-8(7H)-(propyliden-2-yl)-2-naphthalenyl)carbonyl]oxy]-benzoate(Compound E13, 84.0 mg, 0.181 mmol) in 2.0 mL THF at 0° C. was added130.7 mg of tetrabutylammonium fluoride (0.50 mmol; 0.5 mL of a 1Msolution in THF). After stirring at 0° C. for 1.5 h and at roomtemperature for 4.5 h, the reaction was diluted with EtOAc and washedwith H₂O and saturated aqueous NaCl before being dried over MgSO₄. Thesolvents were removed under reduced pressure and the residue crystalizedfrom CH₃CN to give the product as a colorless solid.

[0743]¹H NMR(acetone-d6): δ 1.29 (s, 6H), 1.67 (t, J=6.9 Hz, 2H), 1.87(s, 3H), 1.99 (s, 3H), 2.56 (t, J=6.9 Hz, 2H), 7.43 (d, J=8.6 Hz, 2H),7.54 (d, J=8.2 Hz, 1H), 7.97 (dd, J=1.9, 8.2 Hz, 1H), 8.06 (d, J=1.9 Hz,1H), 8.14 (d, J=8.7 Hz, 2H).

[0744] Ethyl4-[((5,5-dimethyl-8(7H)-(propyliden-2-yl)-5,6-dihydronaphthalen-2-yl)}carbonyl}oxy]benzoate(Compound E15)

[0745] A solution of5,5-dimethyl-5,6-dihydro-8(7H)-(propyliden-2-yl)-2-naphthalenecarboxylicacid (Compound E12, 31.0 mg, 0.127 mmol), ethyl 4-hydroxybenzoate (27.4mg, 0.165 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (31.6 mg, 0.165 mmol), and 4-N,N-dimethylaminopyridine(20.2 mg, 0.165 mmol) in 2.0 mL DMF was stirred overnight at roomtemperature. EtOAc (50 mL) was added and the solution washed with H₂O,5% HCl, saturated aqueous NaCO₃, and saturated aqueous NaCl before beingdried over MgSO₄. Removal of the solvents under reduced pressure andcolumn chromatography (5% EtOAc-hexanes) of the residual oil affordedthe title compound as a colorless oil.

[0746]¹H NMR(CDCl₃): δ 1.28 (s, 6H), 1.41 (t, J=7.1 Hz, 2H), 1.66 (t, tJ=6.9 Hz, 2H), 1.86 (s, 3H, 2.00 (s, 3H), 2.56 (t, J=6.9 Hz, 2H), 4.40(q, J=7.1 Hz, 2H), 7.29 (d, J=8.7 Hz, 2H), 7.43 (d, J=8.1 Hz, 1H), 7.98(dd, J=1.8, 8.1 Hz, 1H), 8.09 (d, J=1.8 Hz, 1H), 8.12 (d, J=8.7 Hz, 2H).

[0747] Ethyl4-[(5,5-dimethyl-8(7H)-(propyliden-2-yl)-5,6-dihydronaphthalen-2-yl}carboxamido]benzoate(Compound E16)

[0748] A solution of1(2H-(propyliden-2-yl)-3,4-dihydro-4,4-dimethylnaphthalene-7-carboxylicacid (Compound E12, 100.0 mg, 0.410 mmol), ethyl 4-aminobenzoate (81.0mg, 0.490 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (117.0 mg, 0.615 mmol), and 4-N,N-dimethylaminopyridine(61.0 mg, 0.500 mmol) in 3.0 mL DMF was stirred overnight at roomtemperature. EtOAc (100 mL) was added and the solution washed with H₂O,10% HCl, saturated aqueous NaCO₃, and saturated aqueous NaC] beforebeing dried over MgSO₄. Removal of the solvents under reduced pressureand column chromatography (10-15% EtOAc-hexanes) of the residual oilafforded the title compound as a colorless solid.

[0749]¹H NMR(CDCl₃): δ 1.29 (s, 6H), 1.40 (t, 3-7.1 Hz, 2H), 1.64 (t,J=7.0 Hz, 2H), 1.86 (s, 3H), 2.00 (s, 3H), 2.52 (t, J=6.6 Hz, 2H), 4.37(q, J=7.1 Hz, 2H), 7.60 (d, J=8.1 Hz, 1H), 7.63 (dd, J=1.8, 8.1 Hz, 1H),7.73 (d, J=8.6 Hz, 2H), 7.75 (d, J=1.8 Hz, 1H), 7.92 (s, 1H), 8.06 (d,J=8.6 Hz, 2H).

[0750]4-[(5,5-Dimethyl-8(7H)-(propyliden-2-yl)-5,6-dihydronaphthalen-2-yl)}carboxamido]benzoicacid (Compound E17)

[0751] To a solution of ethyl4-[(5,5-dimethyl-8(7H)-(propyliden-2-yl)-5,6-dihydronaphthalen-2-yl)}carboxamido]benzoate(Compound E16, 25.0 mg, 0.064 mmol) in 3.0 mL of EtOH and 3.0 mL THF wasadded NaOH (80.0 mg, 2.00 mmol; 2.0 mL of a 1N aqueous solution). Afterstirring overnight at room 4 temperature the reaction was quenched bythe addition of 10% aqueous HCl. The mixture was extracted with EtOAcand the combined organic layers were washed with H₂O and saturatedaqueous NaCl and thereafter dried over Na₂SO₄. Removal of the solventsunder pressure and crystallization from CH₃CN afforded the titlecompound as a colorless solid.

[0752]¹H NMR(acetone-d₆): δ 1.25 (s, 6H), 1.64 (t, J=6.9 Hz, 2H), 1.85(s, 3H), 1.96 (s, 3H), 2.55 (t, J=6.9 Hz, 2H), 7.45 (d, J=8.1 Hz, 1H),7.78 (dd, J=1.9, 8.1 Hz, 1H), 7.88 (d, J=1.9 Hz, 1H), 7.95-8.05 (m, 4H),9.71 (s, 1H).

[0753]Methyl-5,5-dimethyl-5,6-dihydro-8-(phenylthio)-naphthalene-2-carboxylate(Compound E18)

[0754] To a solution ofmethyl-5,5-dimethyl-5,6-dihydro-naphthalen-8(7H)-one-2-carboxylate(Compound E2, 835.0 mg, 3.60 mmol) in 25.0 mL of THF at room temperaturewas added TiCl₄ (670.0 mg, 3.55 mmol). Thereafter a solution ofthiophenol (430.0 mg, 3.90 mmol) and Et₃N (730.0 mg, 7.20 mmol) in 10 mLTHF was added. The resulting brown mixture was stirred for 6 h beforeH₂O was carefully added to quench the reaction. The pruduct wasextracted into Et₂O and the combined organic layers washed withsaturated aqueous NaCl and dried over MgSO₄. Removal of the solventsunder reduced pressure afforded a solid from which the title compoundwas isolated as a yellow solid by column chromatography (5%EtOAc-hexanes).

[0755]¹H NMR (CDCl₃): δ 1.34 (s, 6H), 2.40 (d, J=4.7 Hz, 2H), 3.85 (s,3H), 6.51 (t, J=4.7 Hz, 1H), 7.10-7.36 (m, 5H), 7.38 (d, J=8.1 Hz, 1H),7.88 (dd, J=1.8, 8.0 Hz, 1H), 8.30 (d, J=1.8 Hz, 1H).

[0756] 5,5-Dimethyl-5,6-dihydro-8-(phenylthio)-naphthalene-2-carboxylicAcid (Compound E19)

[0757] To a solution of methyl5,5-dimethyl-5,6-dihydro-8-(phenylthio)-naphthalene-2-carboxylate(Compound E18, 300.0 mg, 0.926 mmol) in 4.0 mL of EtOH and 2.0 mL THFwas added NaOH (200.0 mg, 5.00 mmol; 5.0 mL of a 1N aqueous solution).After stirring overnight at room temperature the reaction was quenchedby the addition of 10% aqueous HCl. The mixture was extracted with EtOAcand the combined organic layers washed with H₂O and saturated aqueousNaCl before being dried over Na₂SO₄. Removal of the solvents underpressure afforded the title compound as a yellow solid.

[0758]¹H NMR(CDCl₃): δ 1.35 (s, 6H), 2.41 (d, J=4.6 Hz, 2H), 6.54 (t,J=4.6 Hz, 1H), 7.10-7.34 (m, 5H), 7.40 (d, J=8.1 Hz, 1H), 7.92 (dd,J=1.8, 8.1 Hz), 8.36 (d, J=1.8 Hz, 1H).

[0759] Ethyl 4-[(5,5-dimethyl-8-(phenalthio)-5,6-dihydronaphthalen-2-yl)lcarboxamido]benzoate (Compound E20)

[0760] A solution of5,5-dimethyl-5,6-dihydro-8-(phenylthio)-naphthalene-2-carboxylic acid(Compound E19, 183.0 mg, 0.580 mmol), ethyl 4-aminobenzoate (107.0 mg,0.650 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(144.0 mg, 0.750 mmol), and 4-dimethylaminopyridine (85.0 mg, 0.700mmol) in 5.0 mL DMF was stirred overnight at room temperature. EtOAc(100 mL) was added and the solution washed with H₂O and saturatedaqueous NaCl before being dried over MgSO₄. Removal of the solventsunder reduced pressure and column chromatography (20% EtOAc-hexanes) ofthe residual oil afforded the title compound as a colorless solid.

[0761]¹H NMR(CDCl₃): δ 1.37 (s, 6H), 1.40 (t, J=7.1 Hz, 3H), 2.45 (d,J=4.7 Hz, 2H), 4.37 (q, J=7.1 Hz, 2H, 6.65 (t, J=4.7 Hz, 1H), 7.17-7.35(m, 5H), 7.45 (d, J=8.1 Hz, 1H), 7.52 (s, 1H), 7.60 (d, J=8.7 Hz, 2H,7.77 (dd, J=1.8, 8.1 Hz, 1H), 7.96 (d, J=2.0 Hz, 1H, 8.03 (d, J=8.7 Hz,2H).

[0762]4-[(5,5-Dimethyl-8-(phenylthio)-5,6-dihydronaphthalen-2-yl)carboxamido]benzoicAcid (Compound E21)

[0763] To a solution of ethyl4-[(5,5-dimethyl-8-(phenylthio)-5,6-dihydronaphthalen-2-yl)}carboxamido]benzoate(Compound E20, 90.0 mg, 0.196 mmol) in 3.0 mL of EtOH and 3.0 mL THF wasadded NaOH (120.0 mg, 3.00 mmol; 3.0 mL of a 1N aqueous solution). Afterstirring overnight at room temperature the reaction was quenched by theaddition of 10% aqueous HCl. The mixture was extracted with EtOAc andthe combined organic layers washed with H₂O and saturated aqueous NaClbefore being dried over Na₂SO₄. Removal of the solvents under pressureafforded the title compound as a pale yellow solid.

[0764]¹H NMR(acetone-d₆): δ 1.36 (s, 6H), 2.46 (d, J=4.7 Hz, 2H), 6.11(t, J=4.7 Hz, 1H), 7.13-7.36 (m, 5H), 7.51 (d, J=8.0 Hz, 1H), 7.85 (dd,J=1.9, 8.0 Hz, 1H), 7.91-8.03 (m, 4H), 8.24 (d, J=1.9 Hz, 1H), 9.67 (s,1H).

[0765]4-[(5,5-Dimethyl-8-(phenylsulfonyl)-5,6-dihydronaphthalen-2-yl)carboxamido]benzoicAcid (Compound E22)

[0766] To a solution of4-[(5,5-dimethyl-8-(phenylsulfonyl)-5,6-dihydronaphthalen-2-yl)carboxamido]benzoicacid (Compound E21, 60.0 mg, 0.140 mmol) in 6.0 mL Et₂O, 3.0 mL CH₂Cl₂,and 2.0 mL THF at 0° C. was added m-chloroperbenzoic acid (57-80%)(74-110 mg, 0.430-0.640 mmol). The resulting solution was warmed to roomtemperature and stirred overnight. Water was added and the mixtureextracted with EtOAc. The combined organic layers were washed with H₂Oand saturated aqueous NaCl before being dried over Na₂SO₄. Removal ofthe solvents under reduced pressure and crystallization of the residuefrom CH₃CN afforded the title compound as a colorless solid.

[0767]¹H NMR (acetone-d₆): δ 1.23 (s, 6H, 2.60 (d, J=4.9 Hz, 2H),7.51-7.62 (m, 5H), 7.89 (dd, J=1.8, 7.9 Hz 1H), 7.94 (s, 1H), 7.95-8.06(m, 6H), 8.61 (d, J=1.9H, 1H).

[0768] Ethyl4-[{(5,5-dimethyl-8-(phenylthio)-5,6-dihydronaphthalen-2-yl)}carbonylyoxy]benzoate(Compound E23)

[0769] A solution of5,5-dimethyl-5,6-dihydro-8-(phenylthio)-naphthalene-2-carboxylic acid(Compound E19, 150.0 mg, 0.484 mmol), ethyl 4-hydroxybenzoate (88.5 mg,0.530 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(120.6 mg, 0.630 mmol), and 4-N,N-dimethylaminopyridine (77.0 mg, 0.630mmol) in 5.0 mL DMF was stirred overnight at room temperature. EtOAc (50mL) was added and the solution washed with H₂O and saturated aqueousNaCl before being dried over MgSO₄. Removal of the solvents underreduced pressure and column chromatography (10-15% EtOAc-hexanes) of theresidual oil afforded the title compound as a colorless solid.

[0770]¹H NMR(CDCl₃): δ 1.37(s, 6H), 1.40 (t, J=7.1 Hz, 3H), 2.44 (d,J=4.8 Hz, 2H), 4.39 (q, J=7.1 Hz, 2H), 6.57 (t, J=4.8 Hz, 1H), 7.15-7.36(m, 7H), 7.45 (d, J=8.1 Hz, 1H), 8.01 (dd, J=1.8, 81.Hz, 1H), 8.10 (d,J=8.7 Hz, 2H), 8.44 (d, J=1.8 Hz, 1H).

[0771] Ethyl4-[{(5,5-dimethyl-8-(phenylsulfonyl)-5,6-dihydronaphthalen-2-yl)}carbonyl}oxy]benzoate(Compound E24)

[0772] A solution of ethyl4-[{(5,5-dimethyl-8-(phenylthio)-5,6-dihydronaphthalen-2-yl)} carbonyl}oxy]benzoate (Compound E23, B 50.0 mg, 0.109 mmol) in 5.0 mL Et₂O at 0°C. was added m-chloroperbenzoic acid (50%) (25 mg, 0.145 mmol). Theresulting solution was warmed to room temperature and stirred overnight.Et₂O was added and the organic layer washed with H₂O, saturated aqueousNaHCO₃, and saturated aqueous NaCl before being dried over Na₂SO₄.Removal of the solvents under reduced pressure and and columnchromatography (20% EtOAc-hexanes) afforded the title compound as acolorless solid.

[0773]¹H NMR (CDCl₃): δ 1.27 (s, 6H), 1.42 (t, J=7.1 Hz, 3H), 2.56 (d,J=4.9 Hz, 2H, 4.40 (q, J=7.1 Hz, 2H), 7.27 (d, J=8.7 Hz, 2H), 7.43-7.57(m, 5H), 8.02 (m, 3H), 8.14 (d, J=8.7 Hz, 2H), 8.68 (d, J=1.7 Hz, 1H).

[0774] 2-(Trimethylsilyl)ethyl4-[{(5,5-dimethyl-8-(phenylthio)-5,6-dihydronaphthalen-2-yl)}carbonyl]oxy]benzoate(Compound E25)

[0775] A solution of5,5-dimethyl-5,6-dihydro-8-(phenylthio)-naphthalene-2-carboxylic acid(Compound E19, 170.0 mg, 0.548 mmol), 2-trimethylsilylethyl4-hydroxybenzoate (130.0 mg, 0.548 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (126.0 mg,0.657 mmol), and 4-N,N-dimethylaminopyridine (74.0 mg, 0.600 mmol) in4.0 mL DMF was stirred overnight at room temperature. EtOAc (100 mL) wasadded and the solution washed with H₂O, 10% HCl, and saturated aqueousNaCl before being dried over MgSO₄. Removal of the solvents underreduced pressure and column chromatography (5% EtOAc-hexanes) of theresidual oil afforded the title compound as a colorless oil.

[0776]¹H NMR(CDCl₃): δ 0.10 (s, 9H), 1.15 (t, J=8.4 Hz, 2H), 1.38 (s,6H), 2.44 (d, J=4.7 Hz, 2H), 4.43 (d, J=8.4H, 2H), 6.58 (t, J=4.7 Hz,1H), 7.16-7.36 (m, 7H, 7.45 (d, J=8.1 Hz, 1H), 8.02 (dd, J=1.8, 8.1 Hz,1H), 8.10 (d, J=8.7 Hz, 2H), 8.45 (d, J=1.8 Hz, 1H).

[0777]4-[{(5,5-Dimethyl-8-(phenylthio)-5,6-dihydronaphthalen-2-yl)}carbonyl}oxy]benzoicAcid (Compound E26)

[0778] To a solution of 2-(trimethylsilyl)ethyl4-[[(5,5-dimethyl-5,6-dihydro-8-(phenylthio)-naphthalen-2-yl)carbonyl]oxy]-benzoate(Compound E25, 200.0 mg, 0.377 mmol) in 2.0 mL THF at 0° C. was addedtetrabutylammonium fluoride (295.5 mg, 1.13 mmol; 1.13 mL of a 1Msolutution in THF). After 2 h the solution was warmed to roomtemperature and stirred overnight. EtOAc was added and the organic layerwashed with H₂O and saturated aqueous NaCl. Removal of the solventsunder reduced pressure and recrystallization of the residue from CH₃CNafforded the title compound as a pale yellow solid.

[0779]¹H NMR(acetone-d₆): δ 1.39 (s, 6H), 2.51 (d, J=4.7 Hz, 2H), 6.67(t, J=4.7 Hz, 1H), 7.19-7.38 (m, 6H), 7.61 (d, J=8.1 Hz, 1H), 8.02 (dd,J=1.8, 8.1 Hz, 1H), 8.12 (d, J=8.6 Hz, 1H), 8.43 (d, J=8.1 Hz, 1H).

[0780]4-[{(5,5-Dimethyl-8-(phenylsulfonyl)-5,6-dihydronaphthalen-2-yl)}carbonyl}oxy]benzoicacid (Compound E27)

[0781] To a solution of4-[[(5,5-dimethyl-5,6-dihydro-8-(phenylthio)-naphthalen-2-yl)carbonyl]oxy]-benzoicacid (Compound E26, 50.0 mg, 0.116 mmol) in 3.0 mL CH₂C₂, and 1.0 mL THFat 0° C. was added m-chloroperbenzoic acid (57-80%) (34-52 mg,0.197-0.299 mmol). The resulting solution was warmed to room temperatureand stirred overnight. Water was added and the mixture extracted withEtOAc. The combined organic layers were washed with H₂O and saturatedaqueous NaCl before being dried over Na₂SO₄. Removal of the solventsunder reduced pressure and crystallization of the residue from CH₃CNafforded the title compound as a colorless solid.

[0782]¹H NMR (acetone-d₆): δ 1.27 (s, 6H), 2.65 (d, J=4.8 Hz, 2H), 7.14(d, J=8.7 Hz, 2H), 7.57-7.68 (m, 5H), 8.03 (m, 3H), 8.17 (d, J=8.7 Hz,2H), 8.77 (d, J=1.8 Hz, 1H).

[0783] Ethyl4-[(5,5-Dimethyl-8(7H)-one-5,6-dihydronaphthalen-2-yl)carboxamido]benzoate(Compound E28)

[0784] To a solution of5,5-dimethyl-5,6-dihydro-8(7H)-one-naphthalene-2-carboxylic acid(Compound E3, 400.0 mg, 1.833 mmol), ethyl 4-aminobenzoate (317.8 mg,1.924 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(386.5 mg, 2.016 mmol), and 4-dimethylaminopyridine (246.3 mg, 2.016mmol) in 18.0 mL CH₂Cl₂ was stirred at room temperature for 2 h. EtOAc(25 mL) was added and the solution washed with H₂O, 1M HCl, andsaturated aqueous NaCl before being dried over MgSO₄. Removal of thesolvents under reduced pressure and column chromatography (30%EtOAc-hexanes) of the residue afforded the title compound as a colorlesssolid.

[0785]¹H NMR(CDCl₃): δ 1.41 (t, J=7.1 Hz, 3H), 1.45 (s, 6H), 2.08 (t,J=7.1 Hz, 2H), 2.80 (t, J=6.6 Hz, 2H), 4.38 (q, J=7.2 Hz, 2H), 7.62 (d,J=8.3 Hz, 1H), 7.78 (d, J=8.7 Hz, 2H), 8.09 (d, J=8.6 Hz, 2H), 8.14 (bs,1H, 8.21 (dd, J=2.1, 8.3 Hz, 1H), 8.42 (d, J=2.1 Hz, 1H).

[0786]4-[(5,5-Dimethyl-8(72-one-5,6-dihydronaphthalen-2-yl)carboxamido]benzoicAcid (Compound E29)

[0787] A solution of ethyl4-[(5,5-dimethyl-8(7H)-one-5,6-dihydronaphthalen-2-yl)carboxamido]benzoate(Compound E28, 50.0 mg, 0.137 mmol) and NaOH (54.7 mg, 1.37 mmol; 0.68mL of a 2N aqueous solution) in 2.0 mL EtOH and 1.0 mL THF was stirredat room temperature overnight. The reaction mixture was acidified with10% HCl and extracted with EtOAc. The combined organic layers werewashed with H₂O and saturated aqueous NaCl before being dried overNa₂SO₄. Removal of the solvents under reduced pressure andcrystallization of the residual solid from MeOH/H₂O afforded the titlecompound as yellow crystals.

[0788]¹H NMR (DMSO-d₆): δ 1.40 (s, 6H), 2.01 (t, J=6.7 Hz, 2H), 2.74 (t,J=7.0 Hz, 2H), 7.74 (d, J=8.4 Hz, 1H), 7.93 (m, 4H), 8.16 (dd, J=2.1,8.3 Hz, 1H), 8.45 (d, J=2.0 Hz, 1H), 10.68 (s, 1H), 12.75 (bs, 1H).

[0789] Ethyl4-[(5,5-dimethyl-8(7H)-anti-(O-methyloxime)-5,6-dihydronaphthalen-2-yl)carboxamido]benzoate(Compound E30)

[0790] A mixture of ethyl4-[(5,5-dimethyl-5,6-dihydro-8(7H)-one-naphthalen-2-yl)carboxamido]-benzoate(Compound E28, 100.0 mg, 0.274 mmol), O-methylhydroxylaminehydrochloride (25.1 mg, 0.301 mmol), and NaOAc)₃H₂O (81.9 mg, 0.602mmol) in 3.0 mL of EtOH was heated to 65° C. for 3 h and then stirred atroom temperature for 68 h. The reaction was diluted with H₂O andextracted with EtOAc. The combined organic layers were washed with H₂Oand saturated aqueous NaCl before being dried over MgSO₄. Removal of thesolvents under reduced pressure and column chromatography (20-30%EtOAc-hexanes) of the residue afforded the title compound as a colorlesssolid.

[0791]¹H NMR (CDCl₃): δ 1.32 (s, 6H), 1.40 (t, J=7.2 Hz, 2H), 1.75 (t,J=7.0 Hz, 2H), 2.81 (t, J=7.0 Hz, 2H), 4.04 (s, 3H), 4.37 (q, =7.1 Hz,2H), 7.49 (d, J=8.2 Hz, 1H), 7.76 (dd, J=1.9, 8.7 Hz, 2H), 7.88 (dd,J=2.1, 8.3 Hz, 1H), 8.06 (dd, J=1.7, 8.7 Hz, 2H), 8.12 (bs, 1H), 8.40(d, J=2.0 HI, 1H).

[0792]4-[(5,5-Dimethyl-8(7H)anti-(O-methyloxime)-5,6-dihydronaphthalen-2-yl)carboxamido]benzoicAcid (Compound E31)

[0793] A solution of ethyl(E)₄-[[(5,5-dimethyl-5,6-dihydro-8(7H)-anti-(O-methyloxime)-naphthalen-2-yl)carboxamido]-benzoate(Compound E30, 31.4 mg, 0.080 mmol) and NaOH (31.8 mg, 0.796 mmol; 0.40mL of a 2N aqueous solution) in 2 mL EtOH was stirred at roomtemperature overnight. The reaction was acidified with 10% HCL andextracted with EtOAc. The combined organic layers were dried (Na₂SO₄)and concentrated under reduced pressure to give an off-white solid.Crystallization from Et₂O afforded the title compound as a colorlesssolid.

[0794]¹H NMR (DMSO-d₆): δ 1.27 (s, 6H), 1.69 (t, J=6.9 Hz, 2H), 2.74 (t,J=6.9 Hz, 2H), 3.96 (s, 3H), 7.58 (d, J=8.3 Hz, 1H), 7.90 (m, 5H), 8.36(d, J=2.0 Hz, 1H), 10.57 (s, 1H), 12.73 (bs, 1H).

[0795] (+/−) Ethyl4-[(5,5-dimethyl-8-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)carboxamido]benzoate(Compound E32)

[0796] A solution of ethyl4-[(5,5-dimethyl-5,6-dihydro-8(7H)-one-naphthalen-2-yl)carboxamido]-benzoate(Compound E28, 125.0 mg, 0.342 mmol) in 2.0 mL EtOH and 2.0 mL THF wascooled to 0° C. and treated with NaBH₄ (11.5 mg, 0.304 mmol). After 4 hthe reaction was quenched by the careful addition of H₂O, followed by0.5 mL 1M HCl. EtOAc (25 mL) was added and the solution washed with 1MHCl, dilute aqueous NaHCO₃, H₂O and saturated aqueous NaCl before beingdried over Na₂SO₄. Removal of the solvents under reduced pressureafforded the title compound as a colorless solid.

[0797]¹H NMR (acetone-d₆): δ 1.28 (s, 3H), 1.31 (s, 3H), 1.35 (t, J=7.2Hz, 3H), 1.65 (m, 1H), 1.88 (m, 3H), 4.32 (q, J=7.1 Hz, 2H), 4.69 (q,J=5.8 Hz, 1H), 7.49 (d, J=8.2, Hz, 1H), 7.83 (dd, J=2.2, 8.3 Hz, 1H),7.99 (s, 4H), 8.09 (d, J=1.9 Hz, 1H), 9.81 (bs, 1H).

[0798] (+/−)4-[(5,5-Dimethyl-8-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)carboxamido]benzoicAcid (Compound E33)

[0799] A mixture of (+/−)ethyl-4-[(5,5-dimethyl-5,6,7,8-tetrahydro-8-hydroxy-naphthalen-2-yl)carboxamido]-benzoate(Compound E32, 50.0 mg, 0.136 mmol) and NaOH (54.4 mg, 1.36 mmol; 0.68mL of a 2N aqueous solution) in 3 mL EtOH was stirred at roomtemperature for 19 h. The resulting solution was acidified with 10% HCland extracted with EtOAc. The combined organic layers wre washed withH₂O and saturated aqueous NaCl, and then dried over Na₂SO₄. Removal ofthe solvents under reduced pressure afforded the title compound as acolorless solid.

[0800]¹H NMR (DMSO-d₆): δ 1.25 (s, 3H), 1.28 (s, 3H), 1.61 (m, 1H), 1.80(m, 2H), 1.95 (m, 1), 4.87 (m, 1), 5.30 (s, 1), 7.49 (d, J=8.2 Hz, 1H),7.78 (dd, J=1.9, 8.2 Hz, 1H), 7.49 (s, 4H), 8.01 (s, 1H), 10.47 (s, 1H),12.72 (bs, 1H).

[0801] (+/−) Ethyl 4-[(5,5-dimethyl-8-(O-methoxymethyl)-5,6,7,8tetrahydronaphthalen-2-yl)carboxamido]benzoate (Compound E34)

[0802] To a solution of (+/−) ethyl4-[(5,5-dimethyl-8-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)carboxamido]benzoate(Compound E32, 57.0 mg, 0.155 mmol) in 5.0 mL CH₂Cl₂ at 0° C. was addeddiisopropylethyl amine (276.2 mg, 2.137 mmol), chloromethyl methyl ether(37.7 mg, 0.469 mmol), and a catalytic amount of tetrabutylammoniumiodide. The resulting solution was stirred at 45° C. overnight. Uponcooling to room temperature the solution was diluted with EtOAc andwashed with 5% HCl, H₂O, saturated aqueous NaHCO₃, and saturated aqueousNaCl, before being dried over MgSO₄. Removal of the solvents underreduced pressure, followed by column chromatography (15% EtOAc-hexanes)afforded the title compound as a colorless oil.

[0803]¹H NMR (CDCl₃): δ 1.27 (s, 3H), 1.35 (s, 3H), 1.39 (t, J=7.1 Hz,3H), 1.64 (m, 1H), 1.90-2.13 (m, 3H), 3.48 (s, 3H), 4.36 (q, J=7.1 Hz,2H), 4.67 (t, J=5.0 Hz, 1H), 4.79 (d, J=6.9 Hz, 1H), 4.89 (d, J=6.9 Hz,1H), 7.43 (d, J=8.2 Hz, 1H), 7.74 (m, 3H), 7.88 (d, J=2.0 Hz, 1H), 8.03(d, J=8.7 Hz, 2H), 8.18 (s, 1H).

[0804] (+/−)4-[(5,5-Dimethyl-8-(O-methoxymethyl)-5,6,7,8-tetrahydronaphthalen-2-yl)carboxamido]benzoicAcid (Compound E35)

[0805] A mixture of(+/−) ethyl4-[(5,5-dimethyl-8-(O-methoxymethyl)-5,6,7,8-tetrahydronaphthalen-2-yl)carboxamido]benzoate(Compound E34, 30.0 mg, 0.073 mmol) and NaOH (40.0 mg, 1.00 mmol; 1.0 mLof a 1N aqueous solution) in 1.0 mL EtOH and 1.0 mL THF was stirred atroom temperature overnight. The resulting solution was acidified with10% HCl and extracted with EtOAc. The combined organic layers wre washedwith H₂O and saturated aqueous NaCl, and then dried over Na₂SO₄. Removalof the solvents under reduced pressure afforded the title compound as acolorless oil.

[0806]¹H NMR (acetone-d₆): S 1.27 (s, 3H), 1.34 (s, 3H), 1.65 (m, 1H),1.95 (m, 2H), 2.08 (m, 1H), 3.42 (s, 3H), 4.66 (t, J=5.0 Hz, 1H), 4.77(d, J=6.9 Hz, 1H), 4.84 (d, J=6.9 Hz, 1H), 7.53 (d, J=8.2 Hz, 1H), 7.86(dd, J=2.0, 8.2 Hz, 1H), 8.00 (m, 5H), 9.78 (s, 1H).

[0807] 2-(Trimethylsilyl)ethyl4-[[(5,5-dimethyl-8(7)-one-5,6-dihydronaphthalen-2-yl)carbonyl]oxy]benzoate(Compound E36)

[0808] To a solution of5,5-dimethyl-5,6-dihydro-8(7H)-one-naphthalene-2-carboxylic acid(Compound E3, 154.0 mg, 0.706 mmol), 2-(trimethylsilyl)ethyl4-hydroxybenzoate (185.0 mg, 0.777 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (176.0 mg,0.918 mmol), and 4-dimethylaminopyridine (112.2 mg, 0.918 mmol) in 4.0mL DMF was stirred at room temperature overnight. EtOAc (100 mL) wasadded and the solution washed with H₂O, 1M HCl, saturated aqueousNaHCO₃, and saturated aqueous NaCl before being dried over MgSO₄.Removal of the solvents under reduced pressure and column chromatography(10% EtOAc-hexanes) of the residue afforded the title compound as acolorless solid.

[0809]¹H NMR(CDCl₃): δ 0.09 (s, 9H), 1.15 (t, J=8.3 Hz, 2H), 1.45 (s,6H), 2.08 (t, J=7.0 Hz, 2H), 2.81 (t, J=7.0 Hz, 2H), 4.43 (t, J=8.3 Hz,2H), 7.28 (d, J=8.7 Hz, 2H), 7.60 (d, J=8.3 Hz, 1H), 8.12 (d, J=8.7 Hz,2H), 8.30 (dd, 1H, J=1.9, 8.3 Hz, 1H), 8.85 (d, J=1.9 Hz, 1H).

[0810] (+/−)₂-Trimethylsilylethyl4-[[(5,5-dimethyl-8-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)carbonyl]oxy]benzoate(Compound E37)

[0811] A solution of 2-(trimethylsilyl)ethyl4-[[(5,5-dimethyl-8(7H-one-5,6-dihydronaphthalen-2-yl)carbonyl]oxy]benzoate(Compound E36, 160.0 mg, 0.365 mmol) in 2.0 mL EtOH and 2.0 mL THF wascooled to 0° C. and treated with NaBH₄ (13.8 mg, 0.365 mmol). After 3 hthe reaction was quenched by the careful addition of 5% aqueous HCl.EtOAc (100 mL) was added and the solution washed with H₂O, diluteaqueous NaHCO₃, and saturated aqueous NaCl before being dried overMgSO₄. Removal of the solvents under reduced pressure followed by columnchromatography (10-15% EtOAc) afforded the title compound.

[0812]¹H NMR (CDCl₃): δ 0.09 (s, 9H), 1.14 (t, J=8.4H, 2H, 1.30 (s, 3H),1.37 (s, 3H), 1.68 (m, 1H), 1.92 (m, 2H), 2.12 (m, 1H), 4.45 (t, J=8.4Hz, 2H), 4.82 (m, 1H), 7.28 (d, J=8.7 Hz, 2H), 7.48 (d, J=8.3 Hz, 1H),8.04 (dd, J=2.0, 8.3 Hz, 1H), 8.11 (d, J=8.7 Hz, 2H), 8.30 (d, J=2.0 Hz,1H).

[0813] +/−) 2-(Trimethylsilyl) ethyl4-[[(5,5-dimethyl-8-(O-methoxymethyl)-5,6,7,8-tetrahydronaphthalen-2-l)carbonyl]oxy]benzoate(Compound E38)

[0814] To a solution of (+/−) 2-trimethylsilylethyl4-[[(5,5-dimethyl-8-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)carbonyl]oxy]benzoate(Compound E37, 70.0 mg, 0.159 mmol) in 5.0 mL CH₂Cl₂ at 0° C. were addeddiisopropylethylamine (276.2 mg, 2.137 mmol), and chloromethyl methylether (37.7 mg, 0.469 mmol). The resulting solution was stirred at roomtemperature overnight. The reaction mixture was diluted with EtOAc andwashed with 5% HCl, H₂O, saturated aqueous NaHCO₃, and saturated aqueousNaCl, before being dried over MgSO₄. Removal of the solvents underreduced pressure, followed by column chromatography (10% EtOAc-hexanes)afforded the title compound as a colorless oil.

[0815]¹H NMR (CDCl₃): δ 0.09 (s, 9H, 1.14 (t, J=8.3H, 2H, 1.30 (s, 3H),1.39 (s, 3H), 1.63 (m, 2H), 1.97 (m, 2H), 3.50 (s, 3H), 4.43 (t, J=8.3Hz, 2H), 4.71 (t, J=5.0 Hz, 1H), 4.81 (d, J=7.0 Hz, 1H), 4.91 d, J=7.0Hz, 1H), 7.28 (d, J=8.7 Hz, 2H), 7.49 (d, J=8.3 Hz, 1H), 8.05 (dd,J=1.8, 8.3 Hz, 1H), 8.10 (d, J=8.7 Hz, 2H), 8.19 (d, J=1.8 Hz, 1H).

[0816] (+/−)4-[[(5,5-dimethyl-8-(O-methoxymethyl)-5,6,7,8-tetrahydronaphthalen-2-yl)carbonyl]oxy]benzoicAcid (Compound E39)

[0817] To a solution of (+/−)2-trimethylsilylethyl-4-[[(5,5-dimethyl-5,6,7,8-tertahydro-8-(O-methoxymethyl)naphthalen-2-yl)carbonyl]oxy]-benzoate(Compound E38, 72.0 mg, 0.148 mmol) in 2.0 mL THF was addedtetrabutylammonium fluoride (130.7 mg, 0.500 mmol; 0.5 mL of a 1Msolution in THF. (The resulting solution was stirred overnight at roomtemperature, diluted with EtOAc, and washed with H₂O and saturatedaqueous NaCl. The solution was dried (MgSO₄) and then concentrated underreduced pressure. The title compound was isolated as a colorless oil bypreparative TLC (5% MeOH—CH₂Cl₂).

[0818]¹H MNR (acetone-d₆): δ 1.30 (s, 3H), 1.37 (s, 3H), 1.67 (m, 1H),1.95 (m, 2H), 2.11 (m, 1H), 3.42 (s, 3H), 4.70 (t, J=5.0 Hz, 1H, 4.88(d, J=7.0 Hz, 2H), 7.42 (d, J=8.7 Hz, 2H), 7.62 (d, J=8.3 Hz, 1H), 7.77(d, J=7.0 Hz, 2H), 8.03 (dd, J=1.9, 8.3 Hz,

[0819] 1H), 8.15 (d, J=8.7 Hz, 2H), 8.19 d, J=1.9 Hz, 1H). (+/−) Ethyl4-[[(5,5-dimethyl-8-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)carbonyl]oxy]benzoicacid (Compound E40)

[0820] A solution of ethyl 4-[[(5,5-dimethyl-5,6-dihydro-8(7H)-onenaphthalen-2-yl)carbonyl]oxy]-benzoate (Compound E44, 126.0 mg, 0.344mmol) in 1.5 mL EtOH and 1.5 mL THF was cooled to 0° C. and treated withNaBH₄ (13.0 mg, 0.344 mmol). After 3 h the reaction was quenched by thecareful addition of H₂O. EtOAc (50 mL) was added and the solution washedwith H₂O and saturated aqueous NaCl before being dried over MgSO₄.Removal of the solvents under reduced pressure followed by columnchromatography (15-20% EtOAc) afforded the title compound as a colorlessoil.

[0821]¹H NMR (CDCl₃): δ 1.30 (s, 3H), 1.37 (s, 3H), 1.41 (t, J=7.1 Hz,3H), 1.68 (m, 1H), 1.83-1.99 (m, 2H), 2.15 (m, 1H), 4.39 (q, J=7.1 Hz,2H), 4.82 (m, 1H), 7.28 (d, J=8.7 Hz, 2H), 7.49 (d, J=8.3 Hz, 1H), 8.05(dd, J=1.8, 8.3 Hz, 1H), 8.12 (d, J=8.7 Hz, 2H), 8.29 (d, J=1.8 Hz, 1H).

[0822] (+/−)Ethyl4-[[(5,5-dimethyl-8-(O-methoxyethyl)-5,6,7,8-tetrahydronaphthalen-2-yl)carbonyl]oxy]benzoate(Compound E41)

[0823] To a solution of (+/−) ethyl4-[[(5,5-dimethyl-5,6,7,8-tetrahydro-8-hydroxy-naphthalen-2-yl)carbonyl]oxy]-benzoate(Compound E40, 131.8 mg, 0.358 mmol) in 5.0 mL CH₂Cl₂ at 0° C. was addeddiisopropylethylamine (277.5 mg, 2.147 mmol), and chloromethyl methylether (86.9 mg, 1.08 mmol). The resulting solution was stirred at roomtemperature overnight. The reaction mixture was diluted with EtOAc andwashed with 10% HCl, H₂O, saturated aqueous NaHCO₃, and saturatedaqueous NaCl, before being dried over MgSO₄. Removal of the solventsunder reduced pressure, followed by column chromatography (15%EtOAc-hexanes) afforded the title compound as a colorless oil.

[0824]¹H NMR (CDCl₃): δ 1.29 (s, 3H), 1.38 (s, 3H), 1.41 (t, J=7.1 Hz,3H),-1.62 (m, 2H), 1.96 (m, 2H), 3.50 (s, 3H), 4.39 (q, J=7.1 Hz, 2H),4.71 (t, J=5.0 Hz, 1H), 4.80 d, J=7.0 Hz, 1H), 4.92 (d, J=7.0 Hz, 1H),7.28 (d, J=8.7 Hz, 2H), 7.49 (d, J=8.3 Hz, 1H), 8.05 (dd, J=1.8, 8.3 Hz,11H), 8.12 (d, J=8.7 , 2H), 8.19 (d, J=1.8 Hz, 1H).

[0825] 2-(Trimethylsilyl)ethyl-4-[[(5,5-dimethyl-8()anti-(O-methyloxime)-5,6-dihydronaphthalen-2-yl)carbonyl]oxy]benzoate(Compound E42)

[0826] A mixture of 2-(trimethylsilyl)ethyl4-[[(5,5-dimethyl-5,6-dihydro-8(7H)-one-naphthalen-2-yl)carbonyl]oxy]-benzoate(Compound E36, 80.0 mg, 0.182 mmol), O-methylhydroxylamine hydrochloride(22.8 mg, 0.273 mmol), and NaOAc) X 3H₂O (62.0 mg, 0.455 mmol) in 3.0 mLof EtOH was stirred at room temperature for 5 days. The reaction wasdiluted with H₂O and extracted with EtOAc. The combined organic layerswere washed with H₂O and saturated aqueous NaCl before being dried overMgSO₄. Removal of the solvents under reduced pressure and columnchromatography (4-8% EtOAc-hexanes) of the residue, followed bypreparative TLC (20% EtOAc-hexanes, afforded the title compound.

[0827]¹H NMR (CDCl₃): δ 0.09 (s, 9H), 1.14 (t, J=8.6 Hz, 2H), 1.33 (s,6H), 1.76 (t, J=6.9 Hz, 2H), 2.82 (t, J=6.9 Hz, 2H), 4.04 (s, 3H), 4.43(q, J=8.4 Hz, 2H), 7.30 (d, J=8.7 Hz, 2H), 7.49 (d, J=8.3 Hz, 1H), 8.08(dd, J=1.9, 8.3 Hz, 1H), 8.12 (d, J=8.7 Hz, 2H), 8.78 (d, J=1.9 Hz, 1H).

[0828]4-[[(5,5-dimethyl-8(7H)-anti-(O-methyloxime)-5,6-dihydronaphthalen-2-yl)carbonyl]oxy]benzoicAcid (Compound E43)

[0829] To a solution of (trimethylsilyl)ethyl4[[(5,5-dimethyl-8(7H)-anti-(O-methyloxime)-5,6-dihydronaphthalen-2-yl)carbonyl]oxy]benzoate(Compound E42, 40.0 mg, 0.086 mmol) in 1.5 mL THF was addedtetrabutylammonium fluoride (68.0 mg, 0.260 mmol; 0.26 mL of a 1Msolution in THF). The resulting solution was stirred for 6 h at roomtemperature, diluted with EtOAc, and washed with H₂O and saturatedaqueous NaCl. The solution was dried (MgSO₄) and then concentrated underreduced pressure. The title compound was isolated as a colorless oil bypreparative TLC (5% MeOH—CH₂Cl₂).

[0830]¹H NMR (acetone-d₆): δ 1.34 (s, 6H), 1.78 (t, J=7.0 Hz, 2H), 2.81(t, J=7.0 Hz, 2H), 3.98 (s, 3H), 7.45 (d, J=8.7 Hz, 2H), 7.67 (d, J=8.3Hz, 1H), 8.10 (dd, J=1.9, 8.3 Hz, 1H), 8.15 (d, J=8.7 Hz, 2H), 8.74 (d,J=1.9 Hz, 1H).

[0831] Ethyl4-[[(5,5-dimethyl-8H)-one-56.6dihydronaphthalen-2-yl)carbonyl]oxy]benzoate(Compound E44)

[0832] To a solution of5,5-dimethyl-5,6-dihydro-8(7H)-one-2-naphthalenecarboxylic acid(Compound E3, 270.0 mg, 1.24 mmol), ethyl 4-hydroxybenzoate (226.0 mg,1.364 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(309.0 mg, 1.61 mmol), and 4-N,N-dimethylaminopyridine (197.0 mg, 1.61mmol) in 5.0 mL DMF was stirred at room temperature overnight. EtOAc (25mL) was added and the solution washed with H₂O, 1M HCl, and saturatedaqueous NaCl before being dried over MgSO₄. Removal of the solventsunder reduced pressure and column chromatography (7% EtOAc-hexanes) ofthe residue afforded the title compound as a pale-orange solid.

[0833]¹H NMR(CDCl₃): δ 1.41 (t, J=7.1 Hz, 3H), 1.45 (s, 6H), 2.08 (t,J=6.7 Hz, 2H), 2.80 (t, J=6.7 Hz, 2H), 4.39 (q, J=7.1 Hz, 2H), 7.30 (d,J=8.7 Hz, 2H), 7.60 (d, J=8.4 Hz, 1H), 8.13 (d, J=8.7 Hz, 2H), 8.31 (dd,J=1.8, 8.4 Hz, 1H) 8.04 (d, J=1.8 Hz, 1H).

[0834] Ethyl4-[[(5,5-dimethyl-8(7H)-anti-(O-methyloxime)-5,6-dihydronaphthalen-2-yl)carbonyl]oxy]benzoate(Compound E46)

[0835] A mixture of ethyl4-[[(5,5-dimethyl-8(7H)-one-5,6-dihydronaphthalen-2-yl)carbonyl]oxy]benzoate(Compound E44, 66.0 mg, 0.180 mmol), O-methylhydroxylamine hydrochloride(23.0 mg, 0.270 mmol), and NaOAc)₃H₂O (62.0 mg, 0.455 mmol) in 3.0 mL ofEtOH was stirred at room temperature for 6 days. The reaction wasdiluted with H₂O and extracted with EtOAc. The combined organic layerswere washed with H₂O and saturated aqueous NaCl before being dried overMgSO₄. Removal of the solvents under reduced pressure and columnchromatography (4-8% EtOAc-hexanes) of the residue, followed bypreparative TLC (5% EtOAc-hexanes) afforded the title compound.

[0836]¹H NMR (CDCl₃): δ 1.33 (s, 6H), 1.41 (t, J=7.1 Hz, 3H), 1.76 (t,J=6.9 Hz, 2H), 2.82 (t, J=6.9 Hz, 2H), 4.03 (s, 3H), 4.39 (q, J=7.1 Hz,2H), 7.30 (d, J=8.6 Hz, 2H), 7.50 (d, J=8.3 Hz, 1H), 8.11 (dd, J=1.9,8.3 Hz, 1H), 8.13 (d, J=8.6 Hz, 2H), 8.78 (d, J=1.9 Hz, 1H).

[0837] (+/Ethyl 2-(1-hydroxy-1,2,34-tetrahydro-4,4-dimethyl-7-bromo-naphthalen-1-yl)acetate (CompoundE47)

[0838] To a suspension of Zn (1.20 g, 18.4 mmol) in 10 mL benzene at100° C. was slowly added a solution of ethyl 2-bromoacetate (658.0 mg,3.94 mmol) and 3,4-dihydro-4,4-dimethyl-7-bromo-naphthalen-1(2H)-one(Compound G, 500.0 mg, 1.97 mmol) in 20.0 mL benzene. The resultingmixture was heated for 2 h, cooled to room temperature, and the solutiondecanted from the residual solids. The solids were washed with EtOAc andthe combined organic layers were washed with cold 15% H₂SO₄, saturatedaqueous NaHCO₃, and saturated aqueous NaCl before being dried overMgSO₄. Removal of the solvents undr reduced pressure and columnchromatography (10% EtOAc-hexanes) afforded the title compound as ayellow oil.

[0839]¹H NMR (CDCl₃): δ 1.26 (s, 3H), 1.29 (s, 3H), 1.31 (t, J=7.1 Hz,3H), 1.62-1.82 (m, 2H), 2.05 (m, 2H), 2.75 (s, 2H), 4.21 (q, J=7.1 Hz,2H), 7.16 (d, J=8.5 Hz, 1H), 7.33 (dd, J=2.1, 8.5 Hz, 1H), 7.71 (d,J=2.1 Hz, 1H).

[0840] (+/−) Ethyl2-(1-acetoxy-1,2,3,4-tetrahydro-4,4-dimethyl-7-bromo-naphthalen-1-yl)acetate(Compound E48)

[0841] To a solution of (+/−) ethyl2-(1-hydroxy-1,2,3,4-tetrahydro-4,4-dimethyl-7-bromo-naphthalen-1-yl)acetate(Compound E47, 200.0 mg, 0.586 mmol) and 4-N,N-dimethylaminopyridine(86.0 mg, 0.703 mmol) in 4.0 mL CH₂Cl₂ at 0° C. was added aceticanhydride (239.3 mg, 2.344 mmol). The resulting solution was warmed toroom temperature and stirred overnight. The reaction was warmed to 50°C. for 3 h, cooled to room temperature, and diluted with EtOAc (70 mL).The solution was washed with H₂O, saturated aqueous NaHCO₃, 10% aqueousHCl, and saturated aqueous NaCl, before being dried over MgSO₄. Removalof the solvents under reduced pressure followed by column chromatographyafforded the title compound as a colorless oil.

[0842]¹H NMR (CDCl₃): δ 1.23 (t, J=7.1H, 3H), 1.30 (s, 3H), 1.31 (s,3H), 1.76 (t, J=6.9 Hz, 2H), 2.05 (s, 3H), 2.48 (m, 1H), 2.67 (m, 1),3.03 (s, 2H, 4.12 (q, J=7.1 Hz, 2H), 7.19 (d, J=8.5 Hz, 1H), 7.33 (dd,J=2.1, 8.5H, 1H), 7.45 (d, J=2.1 Hz, 1H).

[0843] (+/−) Ethyl4-[(5,5-dimethyl-5,6,7,8-tetrahydro-8-acetoxy-8-carbethoxymethyl-naphthalen-2-yl)carboxamido]-benzoate(Compound E49)

[0844] A solution of ethyl2-(1-acetoxy-1,2,3,4-tetrahydro-4,4-dimethyl-7-bromo-naphthalen-1-yl)acetate(Compound E48, 450.0 mg, 1.23 mmol), ethyl 4-aminobenzoate (810.0 mg,4.90 mmol), 1,3-bis(diphenylphosphino)propane (100.0 mg, 0.245 mmol) in5.0 mL Et₃N, and 10.0 mL DMSO was sparged with CO (g) for 10 minutes. Tothis solution was added bis(triphenylphosphine)palladium(II) chloride(105.0 mg, 0.150 mmol). The solution was placed under 1 atm of CO(balloon) and heated to 75° C. for 4 days. Upon cooling to roomtemperature the mixture was diluted with EtOAc and the solution washedwith 10% HCl, H₂O, and saturated aqueous NaCl before being dried overNa₂SO₄. Removal of the solvents under reduced pressure and columnchromatography (5-25% EtOAc-hexanes) afforded the title compound.

[0845]¹H NMR (CDCl₃): δ 1.20 (t, J=7.1 Hz, 3H), 1.35 (s, 6H), 1.40 (t,J=7.1 Hz, 3H), 1.78 (m, 2H), 2.03 (s, 3H), 2.50 (m, 1), 2.71 (m, 1H),3.12 (m, 2H), 4.11 (q, J=7.1 Hz, 2H), 4.37 (q, J=7.1 Hz, 2H), 7.42 (d,J=8.2 Hz, 1H), 7.70 (dd, J=1.9, 8.2 Hz, 1H), 7.73 (d, J=8.7 Hz, 2H),7.95 (d, J=1.9 Hz, 1H), 8.04 (d, J=8.7 Hz, 2H), 8.20 (s, 1H).

[0846] Ethyl(E)₄-[[(5,5-dimethyl-5,6dihydro-8(7H)-(carbethoxymethylidenyl)-naphthalen-2-yl)carboxamido]-benzoate(Compound E50a(trans));

[0847] Ethyl(Z)-4-[[(5,5-dimethyl-5,6dihydro-8(7H-(carbethoxymethylidenyl)-naphthalen-2-yl)carboxamido]-benzoate(Compound E50a(cis)) and

[0848] Ethyl(E)-4-[[(5,5-dimethyl-5,6dihydro-8-(carbethoxymethyl)-naphthalen-2-yl)carboxamido]-benzoate(Compound E50b)

[0849] To a solution of (+/−) ethyl4-[(5,5-dimethyl-5,6,7,8-tertahydro-8-acetoxy-8-carbethoxymethyl-naphthalen-2-yl)carboxamido]-benzoate(Compound E49, 210.0 mg, 0.438 mmol) in 6.0 mL CH₂Cl₂ was added1,8-diazobicyclo[5.4.0]undec-7-ene (200.0 mg, 1.314 mmol). The resultingsolution was stirred at room temperature for 21 h, diluted with EtOAc,and the combined solution washed with 10% aqueous HCl and saturatedaqueous NaCl before being dried over MgSO₄. Removal of the solventsunder reduced pressure and column chromatography (15% EtOAc-hexanes)afforded pure (Compound 50b)and a mixture of Compound E50a(trans) andCompound E50a(cis). Compound E50a(trans) and Compound E50a(cis) wereisolated using reverse phase HPLC (5% H₂O—CH₃CN), each as a colorlesssolid.

[0850] Compound E50a(trans):

[0851] 1H NMR (CDCl₃): δ 1.30 (s, 6H), 1.31 (t, J=7.1 Hz, 3H), 1.40 (t,J=7.1 Hz, 3H), 1.73 (t, J=6.1 Hz, 2H), 3.21 (t, J=6.1 Hz, 2H), 4.16 (q,J=7.1 Hz, 2H), 4.36 (q, J=7.1 Hz, 2H), 6.35 (s, 1H), 7.46 (d, J=8.1 FL,1H), 7.78 (d, J=8.7 Hz, 2H), 7.82 (dd, J=1.8, 8.1 Hz, 1H, 8.04 (d, J=8.7Hz, 2H, 8.06 (d, J=1.8 Hz, 1H), 8.41 (s, 1H).

[0852] Compound E50a(cis):

[0853]¹H NMR (CDCl₃): δ 1.31 (t, J=7.1 Hz, 3H), 1.34 (s, 6H, 1.40 (t,J=7.1 Hz, 3H), 1.88 (t, J=6.5 Hz, 2H), 2.61 (t, J=6.5 Hz, 2), 4.21 (q,J=7.1 Hz, 2H, 4.37 (q, J=7.1 Hz, 2H), 5.92 (t, J=1.1 Hz, 11H, 7.46 (d,J=8.2 Hz, 1H), 7.77 (d, J=8.7 Hz, 2H), 7.88 (dd, J=1.9, 8.2 Hz, 1Hz,8.06 (d, J=8.7 Hz, 2H), 8.39 (s, 1H).

[0854] (Compound E50b):

[0855]¹H NMR (CDCl₃): δ 1.19 (t, J=7.1 Hz, 3H), 1.28 (s, 6H), 1.39 (t,J=7.1 Hz, 3H), 2.26 (d, J=4.5 Hz, 2H, 3.49 (s, 2), 4.11 (q, J=7.1 Hz,2H), 4.38 (q, J=7.1 h, 2H), 5.97 (t, J=4.5 Hz, 1H), 7.35 (d, J=8.0 Hz,1H), 7.70 (dd, J=1.8, 8.0 Hz, 1H), 7.74 (m, 3H), 8.00 (d, J=8.7 Hz, 2H),8.41 (s, 1H).

[0856](Z)-4-[[(5,5-Dimethyl-5,6-dihydro-8(2H)-(carboxymethylidenyl)-naphthalen-2-yl)carboxamido]-benzoicAcid (Compound E52)

[0857] A solution of ethyl(Z)-4-[(5,5-dimethyl-5,6-dihydro-8(7H)-(carbethoxymethylidenyl)-naphthalen-2-yl)carboxamido]-benzoateCompound E50a(cis), 15.0 mg, 0.034 mmol) and NaOH (80.0 mg, 2.00 mmol;2.0 mL of a 1M aqueous solution) in 2.0 mL EtOH and 1.0 mL THF wasstirred overnight at room temperature. The reaction was quenched by theaddition of 10% HCl and extracted with EtOAc. The combined organiclayers were washed with H₂O and saturated aqueous NaCl, and dried overNa₂SO₄. Removal of the solvents under reduced pressure andcrystallization from CH₃CN afforded the title compound as a colorlesssolid.

[0858]¹H NMR (acetone-d6): δ 1.35 (s, 6H), 1.87 (t, j=6.6 Hz, 2H), 2.61(m, 2H), 5.91 (t, J=1.3 Hz, 175, 7.5 (d, J=8.3 Hz, 1H), 7.91-8.04 (m,5H, 8.29 (d, J=1.9H, 1H), 9.66 (s, 1H).

[0859](E)-4-[[(5,5-Dimethyl-5,6-dihydro-8(7H)-(carboxymethylidenyl)-naphthalen-2-yl)carboxamido]-benzoicAcid (Compound E53)

[0860] A solution of ethyl(E)-4-[(5,5-dimethyl-5,6-dihydro-8(7H)-(carbethoxymethylidenyl)-naphthalen-2-yl)carboxamido]-benzoate(Compound E50a(trans), 20.0 mg, 0.046 mmol) and NaOH (160.0 mg, 4.00mmol; 4.0 mL of a 1M aqueous solution) in 3.0 mL EtOH and 1.0 mL THF wasstirred overnight at room temperature. The reaction was quenched by theaddition of 10% HCl and extracted with EtOAc. The combined organiclayers were washed with H₂O and saturated aqueous NaCl, and dried overNa₂SO₄. Removal of the solvents under reduced pressure andcrystallization from CH₃CN afforded the title compound as a colorlesssolid.

[0861]¹H NMR (acetone-d₆): δ 1.34 (s, 6H), 1.76 (t, J=6.9 Hz, 2H), 3.24(m, 2H), 6.46 (t, J=1.8 Hz, 1H), 7.62 (d, J=8.2 Hz, 1H), 7.95-8.05 (m,5H), 8.29 (d, J=1.9 Hz, 1H), 9.91 (s, 1H).

[0862] (+/−) Ethyl4-[[(5,5-dimethyl-8-hydroxy-8-(carbethoxy-)-5,6,7,8-tetrahydronaphthalen-2-yl)carbonyl]oxy]benzoate(Compound E54)

[0863] To a suspension of Zn (500.0 mg, 7.65 mmol) in 10 mL benzene at100° C. was slowly added a solution of ethyl 2-bromoacetate (150.3 mg,0.900 mmol) and ethyl4-[[(5,5-dimethyl-8(7H)-one-5,6-dihydronaphthalen-2-yl)carbonyl]oxy]benzoate(Compound E44, 110.0 mg, 0.300 mmol) in 10.0 mL benzene. The resultingmixture was heated for 2 h, cooled to room temperature, and the solutiondecanted from the residual solids. The solids were washed with EtOAc andthe combined organic layers washed with cold 15% H₂SO₄, saturatedaqueous NaHCO₃, and saturated aqueous NaCl before being dried overMgSO₄. Removal of the solvents under reduced pressure and columnchromatography (15% EtOAc-hexanes) afforded the title compound as apale-yellow oil.

[0864]¹H NMR (CDCl₃): δ 1.30 (t, J=7.1H, 3H), 1.33 (s, 3H), 1.37 (s,3H), 1.43 (t, J=7.1 Hz, 3H), 1.72-1.90 (m, 2H), 2.11 (m, 2H), 2.84 (m,2H), 4.23 (q, J=7.1 Hz, 2H), 4.31 (s, 1H), 4.39 (q, J=7.1 Hz, 2H), 7.27(d, J=8.8 Hz, 2H), 7.46 (d, J=8.3 Hz, 1H), 8.03 (dd, J=1.8, 8.3 Hz, 1H),8.12 (d, J=8.8 Hz, 2H), 8.43 (d, J=1.8 Hz, 1H).

[0865] Ethyl4-[[(5,5-dimethyl-8-(carbethoxy)-5,6-dihydronaphthalen-2-yl)carbonyl]oxy]benzoate(Compound E55)

[0866] To a solution of (+/−) ethyl4-[[(5,5-dimethyl-8-hydroxy-8-(carbethoxy)-5,6,7,8-tetrahydronaphthalen-2-yl)carbonyl]oxy]benzoate(Compound E54, 35.0 mg, 0.077 mmol) in 10 mL benzene was added acatalytic amount (approximately 2 mg) of p-toluenesulfonic acidmonohydrate. The solution was heated to reflux under a Dean-Stark trapfor 3 h, and then cooled to room temperature and stirred overnight. Thesolvent was removed under reduced pressure and the title compoundisolated from the residue by column chromatography (10% EtOAc-hexanes).

[0867]¹H NMR (CDCl₃): δ 1.21 (t, J=7.1 Hz, 3H), 1.33 (s, 6H), 1.41 (t,J=7.1 Hz, 3H), 2.31 (d, J=4.6 Hz, 2H), 3.54 (s, 2H), 4.14 (q, J=7.1 Hz,2H), 4.39 (q, J=7.1 Hz, 2H), 6.01 (t, J=4.6 Hz, 1H), 7.28 (d, J=8.7 Hz,2H), 7.46 (d, J=8.1 Hz, 1H), 8.00 (d, J=1.7 Hz, 1H), 8.04 (dd, J=1.7,8.1 Hz, 1H), 8.13 (d, J=8.7 Hz, 2H).

[0868] Ethyl 4-[5,6,7,8-tetrahydro-8(R or S)-(2′(R orS)-tetrahydropyranoxy)-5,5-dimethyl-2-napthovloxy]benzoate (CompoundE56a) and

[0869] Ethyl 4-[5,6,7,8-tetrahydro-8(R or S)-(2′(S ortetrahydropyranoxy)-5,5-dimethyl-2-napthoyloxy]benzoate (Compound E56b)

[0870] To a solution of ethyl 4-[5,6,7,8tetrahydro-8(R orS)-hydroxy-5,5-dimethyl-2-napthoyloxy]benzoate (Compound E40, 243 mg,0.66 mmol) in anhydrous CH₂Cl₂ (10 mL) was added 3,4-dihydro-2H-pyran(184 mg, 2.2 mmol) followed by pyridinium p- toluenesulfonate (26 mg,0.1 mmol). The reaction mixture was stirred at ambient temperature for16 h, and diluted with CH₂Cl₂ (20 mL). The mixture was washedsuccessively with water (5 mL), saturated NaHCO₃ (10 mL),water (10 mL)and brine (10 mL). The organic phase was dried over MgSO₄ and thenconcentrated in vacuo to a pale yellow oil. Purification by flash columnchromatography (silica, 20% EtOAc-hexane) followed by HPLC separation(partisil 10, 10% EtOAc-hexane) afforded the title compounds ascolorless oil.

[0871] Ethyl 4-[5,6,7,8-tetrahydro-8(R or S)-(2′(R or S)-tetrahydropyranoxy)-5,5-dimethyl-2-napthoyloxy]benzoate (Compound E56a)

[0872]¹H NMR (CDCl₃): δ 1.28 (s, 3H), 1.35 (s, 3H), 1.37 (t, J=7.1 Hz,3H), 1.51-2.11(m, 10H), 3.54-3.61 (m, 1H), 3.96-4.03 (m, 1H), 4.35 (q,J=7.1 Hz, 2H), 4.70 (t, J=5.0 Hz, 1H), 4.87 (t, J=2.3 Hz, 1H), 7.28 (d,J=8.3 Hz, 2H), 7.45 (d, J=8.2 Hz, 1H), 8.02 (dd, J=1.9, 8.3 Hz, 1H),8.10-8.13 (m, 3H).

[0873] Ethyl 4-[5,6,7,8-tetrahydro-8(R or S)-(2′(S or R)-tetrahydropyranoxy)-5,5-dimethyl-2-napthoyloxy]benzoate (Compound E56b)

[0874]¹H NMR (CDCl₃): δ 1.29 (s, 3H), 1.35 (s, 3H), 1.37 (t, J=7.1 Hz,3H), 1.58-2.10(m, 10H), 3.57-3.63 (m, 1H), 4.01-4.08 (m, 1H), 4.35 (q,J=7.1H, 2H), 4.82 (t, J=4.5, 1H), 4.93 (t, J=3.6 Hz, 1H), 7.26 (d, J=8.3Hz, 2H), 7.44 (d, J=8.2H, 1H), 8.01 (dd, J=1.9, 8.3 Hz, 1H), 8.10 (d,J=8.6 Hz, 2H), 8.37 (d, J=1.8 Hz, 1H).

[0875] Ethyl 4-[5,6,7,8-tetrahydro-8(S or R)-(2′(R orS)-tetrahydropyranoxy)-5,5-dimethyl-2-napthovloxy]benzoate (CompoundE58a) and

[0876] Ethyl 4-[5,6,7,8-tetrahydro-8(S or R)-(2′(S orR)-tetrahydropyranoxy)-5,5-dimethyl-2-napthoyloxy]benzoate (CompoundE58b)

[0877] Employing the same general procedure as for the preparation ofethyl 4-[5,6,7,8-tetrahydro-8(R or S)-2(2′(R orS)-tetrahydropyranoxy)-5,5-dimethyl-2-napthoyloxy]benzoate and ethyl4-[5,6,7,8-tetrahydro-8(R or S)-2(2′(S or R)-tetrahydropyranoxy)-5,5-dimethyl-2-napthoyloxy]benzoate, ethyl4-[5,6,7,8-tetrahydro-8(R orS)-hydroxy-5,5-dimethyl-2-napthoyloxy]benzoate (Compound E40, 222 mg,0.6 mmol) was converted to a mixture of diastereomers using3,4-dihydro-2H-pyran (184 mg, 2.2 mmol) and pyridiniump-toluenesulfonate (26 mg, 0.1 mmol). Purification by flash columnchromatography (silica, 20% EtOAc-hexane) followed by HPLC separation(partisil 10 , 10% EtOAc-hexane) afforded the title compounds ascolorless oils.

[0878] Ethyl 4-[5,6,7,8-tetrahydro-8(S or R)-(2′(R orS)-tetrahydropyranoxy)-5,5-dimethyl-2-napthoyloxy]benzoate (CompoundE58a):

[0879]¹H NMR (CDCl₃): δ 1.29 (s, 3H), 1.35 (s, 3H), 1.37 (t, J=7.1 Hz,3H), 1.52-2.15(m, 10H), 3.54-3.61 (m, 1H), 3.96-4.03 (m, 1H), 4.35 (q,J=7.1 Hz, 2H), 4.70 (t, J=5.0 Hz, 1H, 4.87 (t, J=2.3 Hz, 1H), 7.26 (d,J=8.3 Hz, 2H), 7.46 (d, J=8.3 Hz, 18, .02 (dd, J=1.9, 8.3 Hz, 1H),8.10-8.13 (m, 3H). Ethyl 4-[5,6,7,8-tetrahydro-8(S or R)-(2′(S orR)-tetrahydropyranoxy)-5,5-dimethyl-2-naphthoyloxy]benzoate (CompoundE58b)

[0880]¹H NMR (CDCl₃): δ 1.32 (s, 3H), 1.35 (s, 3H), 1.37 (t, J=7.1 Hz,3H), 1.57-2.10(m, 10H), 3.57-3.64 (m, 1H), 4.01-4.08 (m, 1H), 4.35 (q,J=7.1 Hz, 2H), 4.82 (t, J=4.5 Hz, 1H), 4.94 (t, J=3.6 Hz, 1H), 7.26 (d,J=8.3 Hz, 2H), 7.44 (d, J=8.2 Hz, 1H), 8.00 (dd, J=1.9, 8.3 Hz, 1H),8.10 (d, J=8.6 Hz, 2H), 8.36 (d, J=1.8 Hz, 1H).

[0881] Benzyl 4-[5,6,7,8-tetrahydro-8(R or S)-(2′(R orS)tetrahydropyranoxy)-5,5-dimethyl-2-napthoyloxy]benzoate (CompoundE60a) and

[0882] Benzyl 4-[5,6,7,8-tetrahydro-8(R or S)-(2′(S or)tetrahydropyranoxy)-5,5-dimethyl-2-napthoyloxy]benzoate Compound E60b)

[0883] Employing the same general procedure as for the prepartion ofethyl 4-[5,6,7,8-tetrahydro-8(R or S)-(2′(R orS)-tetrahydropyranoxy)-5,5-dimethyl-2-napthoyloxy]benzoate and ethyl4-[5,6,7,8-tetrahydro-8(R or S)-(2′(S orR)tetrahydropyranoxy)-5,5-dimethyl-2-napthoyloxy]benzoate, benzyl4-[5,6,7,8-tetrahydro-8(R orS)-hydroxy-5,5-dimethyl-2-napthoyloxy]benzoate (Compound E82, 142 mg,0.3 mmol) was converted to a mixture of diastereomers using3,4-dihydro-2H-pyran (184 mg, 2.2 mmol) and pyridiniump-toluenesulfonate (26 mg, 0.1 mmol). Purification by lash columnchromatography (silica, 20% EtOAc-hexane) followded by HPLC separation(partisil 10 PAC, 10% EtOAc-hexane) afforded the title compounds ascolorless oil.

[0884] Benzyl 4-[5,6,7,8-tetrahydro-8(R or S)-(2′(R orS)tetrahydropyranoxy)-5,5-dimethyl-2-napthoyloxy]benzoate (Compound 60a)

[0885]¹H NMR (CDCl₃): δ 1.30 (s, 3H), 1.37 (s, 3H), 1.54-2.16 (m, 10H),3.55-3.63 (m, 1H), 3.98-4.05 (m, 1H), 4.72 (t, J=4.9 Hz, 1H), 4.89 (t,J=4.6 Hz, 1H), 5.39 (s, 2H), 7.28 (d, J=8.6 Hz, 2H, 7.31-7.50 (m, 6H),8.03 (dd, J=1.9, 8.3 Hz, 1H), 8.12-8.18 (m, 3H).

[0886] Benzyl 4-[5,6,7,8-tetrahydro-8(R or S)-(2′(S orR)tetrahydropyranoxy)-5,5-dimethyl-2-napthoyloxy]benzoate (CompoundE60b)

[0887]¹H NMR (CDCl₃): δ 1.30 (s, 3H), 1.35 (s, 3H), 1.54-2.08 (m, 10H),3.57-3.64 (m, 1H), 4.01-4.08 (m, 1), 4.82 (t, J=4.4 Hz, 1H), 4.94 (t,J=3.9 Hz, 1H), 5.37 (s, 2H), 7.27 (d, J=6.8 Hz, 2H), 7.34-7.47 (m, 6H),8.00 (dd, J=2.0, 8.3 Hz, 1H), 8.10 (d, J=9.2 Hz, 2H), 8.36 (d, J=1.9 Hz,1H).

[0888] Benzyl 4-[5,6,7,8-tetrahydro-8(S or R)-(2′(R orS)tetrahydropyranoxy)-5,5-dimethyl-2-napthoyloxy]benzoate (CompoundE62a) and

[0889] 1Benzyl 4-[5,6,7,8-tetrahydro-8(S or R)-(2′(S orR)tetrahydropyranoxy)-5,5-dimethyl-2-napthoyloxy]benzoate (CompoundE62b)

[0890] Employing the same general procedure as for the prepartion ofethyl 4-[5,6,7,8-tetrahydro-8(R or S)-(2′(R orS)-tetrahydropyranoxy)-5,5-dimethyl-2-napthoyloxy]benzoate and ethyl4-[5,6,7,8tetrahydro-8(R or S)-(2′(S orR)-tetrahydropyranoxy)-5,5-dimethyl-2-napthoyloxy]benzoate, benzyl4-[5,6,7,8-tetrahydro-8(R orS)-hydroxy-5,5-dimethyl-2-napthoyloxy]benzoate (Compound E82, 142 mg,0.3 mmol) was converted to a mixture of diastereomers using3,4-dihydro-2H-pyran (184 mg, 2.2 mmol) and pyridiniump-toluenesulfonate (26 mg, 0.1 mmol). Purification by flash columnchromatography (silica, 20% EtOAc-hexane) followed by HPLC separation(partisil 10 PAC, 10% EtOAc-hexane) afforded the title componds ascolorless oils. Separation of the diastereomers gave a 1:1 ratio of thetitle compounds both as colorless oils (RT=32 minutes and 39 minutes),respectively.

[0891] Benzyl 4-[5,6,7,8-tetrahydro-8(S or R)-(2′(R orS)tetrahydropyranoxy)-5,5-dimethyl-2-napthoyloxy]benzoate (CompoundE62a):

[0892]¹H NMR (CDCl₃): δ 1.30 (s, 3H), 1.37 (s, 3H), 1.52-2.15 (m, 10H),3.54-3.61 (m, 1H), 3.96-4.03 (m, 1H), 4.70 (t, J=5.0 Hz, 1H), 4.87 (t,J=4.5 Hz, 1H), 5.37 (s, 2H), 7.26 (d, J=6.7 Hz, 2H), 7.29-7.49 (m, 6H),8.02 (dd, J=1.9, 8.3 Hz, 1H), 8.10-8.17 (m, 3H).

[0893] Benzyl 4-[5,6,7,8-tetrahydro-8(S or R)-(2′(S or R)tetrahydropyranoxy)-5,5-dimethyl-2-napthoyloxy]benzoate (Compound E62b):

[0894]¹H NMR (CDCl₃): δ 1.30 (s, 3H), 1.35 (s, 3H), 1.54-2.10 (m, 10H),3.57-3.64 (m, 1H), 4.01-4.08 (m, 1H), 4.82 (t, 4.7 Hz, 1H), 4.94 (t,J=3.5 Hz, 1H), 5.37 (s, 2H, 7.27 (d, J=6.8 Hz, 2H), 7.34-7.47 (m, 6H),8.00 (dd, J=2.0, 8.3 Hz, 1H), 8.10 (d, J=9.2 Hz, 2H), 8.36 (d, J=1.9 Hz,1H).

[0895] 4-[5,6,7,8-tetrahydro-8(R or S)-(2′(R orS)tetrahydropyranoxy)-5,5-dimethyl-2-napthoyloxy]benzoic Acid (CompoundE64)

[0896] To a solution of benzyl 4-[5,6,7,8-tetrahydro-8(R or S)-(2′(R orS)tetrahydropyranoxy)-5,5-dimethyl-2-napthoyloxy]benzoate (CompoundE60a, 15 mg, 0.03 mmol) in ethyl acetate (5 mL) was added a catalyticamount of 10% Pd/C. The reaction mixture was then placed under a blanketof H₂ by using a H₂ balloon and stirred at ambient temperature for 12 h.The reaction mixture was then filtered through a plug of MgSO₄ and thefiltrate was concentrated under reduced pressure to give a white solid.Recrystallization from acetonitrile gave the title compound as a whitesolid.

[0897]¹H NMR (CDCl₃): δ 1.30 (s, 3H), 1.37 (s, 3H), 1.51-2.17 (m, 10H),3.57-3.64 (m, 1H), 3.98-4.06 (m, 1H), 4.72 (t, J=4.9 Hz, 1H), 4.90 (t,J=4.6 Hz, 1H), 7.31 (dd, J=2.5, 9.3 Hz, 2H), 7.48 (d, j=8.3 Hz, 1H),8.04 (dd, J=1.9, 8.3 Hz, 1H), 8.13 (d, J=1.7 Hz, 1H), 8.17 (dd, j=2.4,9.3 Hz, 2H). 4-[5,6,7,8-tetrahydro-8(R or S)-(2′(S orR)tetrahydropyranoxy)-5,5-dimethyl-2-napthoyloxy]benzoic Acid (CompoundE65)

[0898] Employing the same general procedure as for the preparation of4-[5,6,7,8-tetrahydro-8(R or S)-(2′(R orS)tetrahydropyranoxy)-5,5-dimethyl-2-napthoyloxy]benzoic acid (CompoundE64), benzyl 4-[5,6,7,8-tetrahydro-8(R or S)-(2′(S orR)tetrahydropyranoxy)-5,5-dimethyl-2-napthoyloxy]benzoate (CompoundE60b, 15 mg, 0.03 mmol) was converted to the title compound (whitesolid).

[0899]¹H NMR (CDCl₃): δ 1.30 (s, 3H), 1.36 (s, 3H), 1.55-2.11 (m, 10H),3.59-3.64 (m, 1H), 4.02-4.10 (m, 1), 4.83 (t, J=5.0 Hz, 1H), 4.95 (t,J=3.7 Hz, 1H), 7.29 (d, J=8.7H, 2H), 7.4 (d, J=8.3 Hz, 1H), 8.01 (dd,J=1.8, 8.2 Hz, 1H, 8.16 (d, J=8.6 Hz, 2H), 8.37 (d, J=2.0 Hz, 1H).

[0900] 4-[5,6,7,8-tetrahydro-8(R or S)-(2′(R orS)tetrahydropyranoxy)-5,5-dimethyl-2-napthoyloxy]benzoic Acid (CompoundE66)

[0901] Employing the same general procedure as for the preparation of4-[5,6,7,8-tetrahydro-8(R or S)-(2′(R orS)tetrahydropyranoxy)-5,5-dimethyl-2-napthoyloxy]benzoic acid (CompoundE64), benzyl 4-[5,6,7,8-tetrahydro-8(S or R)-(2′(R orS)tetrahydropyranoxy)-5,5-dimethyl-2-napthoyloxy]benzoate (CompoundE62a, 15 mg, 0.03 mmol) was converted to the title compound (whitesolid).

[0902]¹H NMR (CDCl₃): δ 1.29 (s, 3H), 1.36 (s, 3H), 1.53-2.15 (m, 10H),3.56-3.63 (m, 1H), 3.97-4.04 (m, 1H), 4.71 (t, J=4.9 Hz, 1H), 4.89 (t,J=4.3 Hz, 1H), 7.30 (d, J=8.8 Hz, 2H), 7.47 (d, J=8.4 Hz, 1H), 8.03 (dd,J=1.9, 8.2 Hz, 1H), 8.11 (d, J=2.0 Hz, 1H), 8.17 (d, J=8.6 Hz, 2H).

[0903] 4-[5,6,7,8-tetrahydro-8(S or R)-(2′(S orR)tetrahydropyranoxy)-5,5-dimethyl-2-napthoyloxy]benzoic Acid (CompoundE67)

[0904] Employing the same general procedure as for the preparation of4-[5,6,7,8-tetrahydro-8(R or S)-(2′(R or S)tetrahydropyranoxy)-5,5-dimethyl-2-napthoyloxy]benzoic acid (CompoundE64) benzyl 4-[5,6,7,8-tetrahydro-8(S or R)-(2′(S orR)tetrahydropyranoxy)-5,5-dimethyl-2-napthoyloxy]benzoate (CompoundE62b, 15 mg, 0.03 mmol) was converted to the title compound (whitesolid).

[0905]¹H NMR (CDCl₃): δ 1.31 (s, 3H), 1.37 (s, 3H), 1.55-2.09 (m, 10H),3.60-3.65 (m, 1H), 4.04-4.10 (m, 1H), 4.85 (t, J=4.8 Hz, 1H), 4.96 (t,J=3.8 Hz, 1H), 7.31 (d, J=8.6 Hz, 2H), 7.46 (d, J=8.3 Hz, 1H), 8.03 (dd,J=1.9, 8.2 Hz, 1H), 8.18 (d, J=8.6H, 2H), 8.38 (d, J=1.7 Hz, 1H).

[0906] Ethyl 4-[5,6,7,8-tetrahydro-8(S or R)-(2′(R orS)tetrahydropyranoxy)_(5,5)-dimethylnaphthalene-2-yl)carboxamido]benzoate(Compound E70a) and

[0907] Ethyl 4-[5.6,7,8-tetrahydro-8(S or R)-(2′(S orR)tetrahydropyranoxy)5,5-dimethylnaphthalene-2-yl)carboxamido]benzoate(Compound E70b)

[0908] Employing the same general procedure as for the prepartion ofethyl 4-[5,6,7,8-tetrahydro-8(R or S)-(2′(R orS)-tetrahydropyranoxy)-5,5-dimethyl-7napthoyloxy]benzoate and ethyl4-[5,6,7,8-tetrahydro-8(R or S)-(2′(S orR)-tetrahydropyranoxy)-5,5-dimethyl-7-napthoyloxy]benzoate, (+/−) ethyl4-[(5,5-dimethyl-8-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)carboxamido]benzoate(Compound E32, 142 mg, 0.3 mmol) was converted to a mixture ofdiastereomers using 3,4-dihydro-2H-pyran (184 mg, 2.2 mmol) andpyridinium p-toluenesulfonate (26 mg, 0.1 mmol). Purification by flashcolumn chromatography (silica, 20% EtOAc-hexane) followed by HPLCseparation (partisil 10 PAC, 20% EtOAc-hexane) of the diastereomers gavea 1:1 ratio of the title compounds, both as colorless oil (RT=53 minutesand 60 minutes), respectively.

[0909] Ethyl 4-[5,6,7,8-tetrahydro-8(S or R)-(2′(R orS)tetrahydropyranoxy)5,5-dimethylnaphthalene-2-yl)carboxamido]benzoate(Compound E70a):

[0910]¹H NMR (CDCl₃): δ 1.24 (s, 3H), 1.30 (s, 3H), 1.34 (t, J-7.1 Hz,3H), 1.48-2.10 (m, 10H), 3.52-3.56 (m, 1H), 3.92-3.98 (m, 1H), 4.30 (t,J=7.1 Hz, 2H), 4.61 (t, J=4.8 Hz, 1H), 4.80 (t, J=4.5 Hz, 1H), 7.36 (d,J=8.2 Hz, 1H), 7.68-7.74 (m, 3H), 7.80 (d, J=1.9 Hz, 1H), 7.98 (d, J=8.7Hz, 2H), 8.28 (s, 1H).

[0911] Ethyl 4-[5,6,7,8-tetrahydro-8(S or R)-(2′(S orR)tetrahydropyranoxy)5,5-dimethylnaphthalene-2-yl)carboxamido]benzoate(Compound 70b):

[0912]¹H NMR (CDCl₃): δ 1.26 (s, 3H), 1.32 (s, 3H), 1.36 (t, J=1 Hz,3H), 1.58-2.04 (m, 10H, 3.57-3.61 (m, 1H), 4.00-4.05 (m, H), 4.31 (t,J=7.1 Hz, 2H), 4.78 (t, J=4.9 Hz, 1H), 4.86 (t, J=4.6 Hz, 1H), 7.37 (d,J=8.2HI, 1H), 7.73-7.75 (m, 3H), 8.00-8.03 (m, 3H), 8.34 (s, 1H).

[0913] Ethyl 4-[5,6,7,8-tetrahydro-8(R or S)-(2′(R orS)tetrahydropyranoxy)5,5-dimethylnaphthalene-2-yl)carboxamido]benzoate(Compound E72a) and

[0914] Ethyl 4-[5,6,7,8-tetrahydro-8(R or S)-(2′(S ortetrahydropyranoxy)5,5-dimethylnaphthalene-2-yl)carboxamido]benzoate(Compound E72b)

[0915] Employing the same general procedure as for the preparation ofethyl 4-[5,6,7,8-tetrahydro-8-(R or S)-(2′(R orS)-tetrahydropyranoxy)-5,5-dimethyl-7-napthoyloxy]benzoate and ethyl4-[5,6,7,8-tetrahydro-8(R or S)-(2′(S orR)-tetrahydropyranoxy)-5,5-dimethyl-7-napthoyloxy]benzoate, ethyl4-[5,6,7,8-tetrahydro-8(R orS)-hydroxy-5,5-dimethylnaphthalene-2-yl)carboxamido]benzoate (CompoundE32, 142 mg, 0.3 mmol) was converted to a mixture of diastereomers using3,4-dihydro-2H-pyran (184 mg, 2.2 mmol) and pyridiniump-toluenesulfonate (26 mg, 0.1 mmol). Purification by flash columnchromatography (silica, 20% EtOAc-hexane) followed by HPLC separation(partisil 10 PAC, 20% EtOAc-hexane) afforded the title compounds ascolorless oil.

[0916] Ethyl 4-[5,6,7,8-tetrahydro-8(R or S)-(2′(R orS)tetrahydropyranoxy)5,5-dimethylnaphthalene-2-yl)carboxamido]benzoate(Compound E72a):

[0917]¹H NMR (CDCl₃): δ 1.25 (s, 3H, 1.32 (s, 3H, 1.35 (t, J=7.1 Hz,3H), 1.54-2.10 (m, 10H), 3.53-3.60 (m, 1H), 3.94-4.01 (m, 1H), 4.31 (t,J=7.1 Hz, 2H), 4.64 (t, J=4.9 Hz, 1H), 4.83 (t, J=4.3 Hz, 1H), 7.39 (d,J=8.2 Hz, 1H), 7.68-7.73 (m, 3H), 7.80 (d, J=1.8 Hz, 1H), 8.01 (d, J=8.7Hz, 2H), 8.12 (s, 1H).

[0918] Ethyl 4-[5,6,7,8-tetrahydro-8(R or S)-(2′(S orR)tetrahydropyranoxy)5,5-dimethylnaphthalene-2-yl)carboxamido]benzoate(Compound E72b)

[0919]¹H NMR (CDCl₃): δ 1.29 (s, 3H), 1.34 (s, 3H), 1.37 (t, J=7.1 Hz,3H), 1.56-2.10 (m, 10H), 3.58-3.65 (m, 1H), 4.01-4.08 (m, 1H), 4.33 (t,J=7.1 Hz, 2H), 4.81 (t, J=4.9 Hz, 1H), 4.88 (t, J=4.6 Hz, 1H), 7.42 (d,J=8.3 Hz, 1H), 7.72-7.78 (m, 3H), 8.02-8.07 (m, 3H), 8.11 (s, 1H.

[0920] 4-[5,6,7,8-tetrahydro-8(S or R)-(2′(R orS)tetrahydropyranoxy)5,5-dimethyl-naphthalene-2-yl)carboxamido]benzoicAcid (Compound E74)

[0921] To a solution of ethyl 4-[5,6,7,8-tetrahydro-8(S or R)-(2′(R orS) tetrahydropyranoxy)5,5-dimethylnaphthalene-2-yl)carboxamido]benzoate(Compound E70a, 54 mg, 0.12 mmol) in THF (2 mL) and methanol (1 mL) wasadded 0.5 M lithiumhydroxide (2 mL, 1 mmol). The reaction mixture wasstirred at ambient temperature for 12 h. The reaction mixture wasdiluted with EtOAc (15 mL), and acidified with 10% HC to pH 4. Theorganic layer was washed with water (5 mL), brine (10 mL), dried (MgSO₄)and the solvent removed under reduced pressure. Recrystallization fromEtOAc/hexane afforded the title compound as a white solid.

[0922]¹H NMR (acetone-d₆): δ 1.27 (s, 3H), 1.33 (s, 3H), 1.49-2.11 (m,10H), 2.80 (br, 1H), 3.51-3.58 (m, 1H), 3.89-3.96 (m, 1H), 4.67 (t,J=4.4 Hz, 1H), 4.89 (t, J=4.5 Hz, 1H), 7.52 (d, J=8.2 Hz, 1H), 7.80 (d,J=1.9 Hz, 1H), 7.91-8.04 (m, 5H), 9.73 (s, 1H).4-[5,6,7,8-tetrahydro-8(S or R)-(2′(S orR)tetrahydropyranoxy)5,5-dimethyl-naphthalene-2-yl)carboxamido]benzoicacid (Compound E75)

[0923] Employing the same general procedure as for the preparation of4-[5,6,7,8-tetrahydro-8(S or R)-(2′(R orS)tetrahydropyranoxy)5,5-dimethyl-naphthalene-2-yl)carboxamido]benzoicacid (Compound E74) ethyl 4-[5,6,7,8-tetrahydro-8(S or R)-(2′(S orR)tetrahydropyranoxy)5,5-dimethyl-naphthalene-2-yl)carboxamido]benzoate(Compound E70b, 36 mg, 0.08 mmol) was converted into the title compound(white solid).

[0924]¹H NMR (acetone-d6): δ 1.28 (s, 3H, 1.34 (s, 3H), 1.51-2.02 (m,10H, 2.80 (br, 1H), 3.55-3.60 (m, 1H), 3.96-4.03 (m, 1H), 4.77 (t, J=5.4Hz, 1H), 4.92 (t, J=3.8 Hz, 1H), 7.50 (d, J=8.3H, 1H), 7.82 (dd, J=2.0,8.3 Hz, 1H), 7.97-8.02 (m, 4H), 8.09 (d, J=1.9 Hz, 1H), 9.77 (s, 1H).

[0925] 4-[5,6,7,8-tetrahydro-8(R or S)-(2′(R orS)tetrahydropyranoxy)5,5-dimethyl-naphthalene-2-yl)carboxamido]benzoicAcid (Compound E76)

[0926] Employing the same general procedure as for the preparation of4-[5,6,7,8-tetrahydro-8(S or R)-(2′(R orS)tetrahydropyranoxy)-5,5-dimethyl-naphthalene-2-yl)carboxamido]benzoicacid (Compound E74), ethyl 4-[5,6,7,8-tetrahydro-8(R or S)-(2′(S orR)tetrahydropyranoxy)5,5-dimethyl-naphthalene-2-yl)carboxamido]benzoate(Compound E72b, 36 mg, 0.08 mmol) was converted into the title compound(white solid).

[0927]¹H NMR (CDCl₃): δ 1.28 (s, 3H), 1.34 (s, 3H), 1.55-2.08 (m, 10H),3.59-3.65 (m, 1H), 4.04-4.12 (m, 1H), 4.82 (t, J=4.9 Hz, 1H), 4.88 (t,J=2.6 Hz, 1H), 7.43 (d, J=8.3 Hz, 1H), 7.74-7.81 (m, 3H), 8.02 (d, J=1.8Hz, 1H), 8.06 (d, J=8.7w, 2H), 8.30 (s, 1H).

[0928] 4-[5,6,7,8-tetrahydro-8(R or S)-(2′(S orR)tetrahydropyranoxy)5,5-dimethyl-naphthalene-2-yl)carboxamido]benzoicAcid (Compound E77)

[0929] Employing the same general procedure as for the preparation of4-[5,6,7,8-tetrahydro-8(S or R)-(2′(R orS)tetrahydropyranoxy)5,5-dimethyl-naphthalene-2-yl)carboxamido]benzoicacid (Compound E74), ethyl 4-[5,6,7,8-tetrahydro-8(R or S)-(2′(S orR)tetrahydropyranoxy)5,5-dimethyl-naphthalene-2-yl)carboxamido]benzoate(Compound E72a, 36 mg, 0.08 mmol) was converted into the title compound(white solid).

[0930]¹H NMR (CDCl₃): δ 1.27 (s, 3H), 1.34 (s, 3H), 1.55-2.13 (m, 10H),3.57-3.63 (m, 1H), 3.97-4.03 (m, 1H), 4.70 (t, J=4.7 Hz, 1H), 4.89 (t,J=2.4 Hz, 1H), 7.44 (d, J=8.3 Hz, 1H), 7.72-7.77 (m, 3H), 7.82 (d, J=1.9Hz, 1H), 8.06-8.10 M, 3H).

[0931]5,5-dimethyl-5,6-dihydro-8-(1,1-dimethylethyl)-2-naphthalenecarboxylicAcid (Compound E78)

[0932] A solution of7-bromo-1-(1,1-dimethylethyl)-3,4-dihydro-4,4-dimethylnaphthalene(Compound C42, 450.0 mg, 1.54 mmol) in 20 mL of THF was cooled to −78°C. and 197.3 mg (3.08 mmol; 1.8 mL of a 1.7M solution in pentane) addedgiving a pale-yellow solution. After 1 h, CO₂ (from evaporation of DryIce, dried with CaSO₄) was bubbled through the solution for 1 h. Afterstirring at −78° C. for an additional hour, the reaction was quenchedwith 10% aqueous HCl. The solution was extracted with EtOAc and thecombined organic layers washed with H₂O and saturated aqueous NaClbefore being dried over Na₂SO₄. Removal of the solvents under reducedpressure, and washing of the residue with hexanes afforded the titlecompound as a colorless solid.

[0933]¹H NMR (CDCl₃) δ: 1.25 (6H, s), 1.38 (9H, s), 2.17 (2H, d, J=264.9Hz), 6.02 (1H, t, J=4.9 Hz), 7.41 (1H, d, J=8.1 Hz), 7.91 (1H, dd,J=1.6, 8.1 Hz), 8.42 (1H, d, J=1.6 Hz).

[0934] Ethyl4-[(5,5-dimethyl-5,6-dihydro-8-(1,1-dimethylethyl)-2-naphthalenyl)carboxamido]-benzoate(Compound E79)

[0935] A solution of5,5-dimethyl-5,6-dihydro-8-(1,1-dimethylethyl)-2-naphthalenecarboxylicacid (Compound E78, 150.0 mg, 0.581 mmol), ethyl 4-aminobenzoate (115.2mg, 0.697 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (145.0 mg, 0.755 mmol), and 4-N,N-dimethylaminopyridine(89.0 mg, 0.697 mmol) in 8.0 mL DMF was stirred overnight at roomtemperature. EtOAc (110 mL) was added and the solution washed with H₂O,5% HCl, saturated aqueous NaHCO₃, and saturated aqueous NaCl beforebeing dried over MgSO₄. Removal of the sovents under reduced pressureand column chromatography (10-25% EtOAc-hexanes) of the residual oilafforded the title compound as a colorless solid.

[0936]¹H NMR(CDCl₃) δ 1.25 (6H, s), 1.39 (9H, s), 1.40 (3H, t, J=7.1Hz), 2.18 (2H, d, JT=4.9 Hz), 4.37 (2H, q, J=7.1 Hz), 6.05 (1H, t, J=4.9Hz), 7.41 (1H, d, J=8.0 Hz), 7.58 (1H, dd, J=1.8, 8.0 Hz), 7.24 (2H, d,J=8.7 Hz), 7.91 (1H, s,), 8.06 (2H, d, J=8.7 Hz), 8.26 (1H, d, J=1.8Hz).

[0937]4-[(5,5-dimethyl-5,6-dihydro-8-(1,1-dimethylethyl)-2-naphthalenyl)carboxamido]-benzoicAcid (Compound E80)

[0938] To a solution of ethyl4-[(5,5-dimethyl-5,6-dihydro-8-(1,1-dimethylethyl)-2-naphthalenyl)carboxamido]-benzoate(Compound E79, 50.0 mg, 0.123 mmol) in 2.0 mL of EtOH and 3.0 mL THF wasadded NaOH (240.0 mg, 6.00 mmol; 3.0 mL of a 2N aqueous solution). Afterstirring overnight at room temperature the reaction was quenched by theaddition of 1M aqueous HCl. The mixture was extracted with EtOAc and thecombined organic layers washed with H₂O and saturated aqueous NaClbefore being dried over Na₂SO₄. Removal of the solvents under reducedpressure afforded the title compound as a colorless solid.

[0939]¹H NMR(d₆-acetone) δ 1.24 (6H, s), 1.38 (9H, s), 2.17 (2H, d,J=4.9 Hz), 6.08 (1H, t, J=4.9 Hz), 7.45 (1H, d, J=8.1 Hz), 7.81 (1H, dd,J=1.8, 8.1 Hz), 7.97-8.05 (4H, m), 8.31 (1H, d, J=1.8 Hz).

[0940]Benzyl-4-[[(5,5-dimethyl-5,6,7,8-tetrahdro-8-oxo-naphthalen-2-yl)carbonyl]oxy]-benzoate(Compound E81)

[0941] To a solution of5,5-dimethyl-5,6,7,8-tetrahydro-8-oxo-naphthalen-2-carboxylic acid(Compound E3, 386 mg, 1.77 mmol) in dimethylformamide (4 mL) was added1-(3-dimethylaminopropyl)-3-ethylcarboimide hydrochlorde (440 mg, 2.3mmol) followed by dimethylamino pyridine (DMAP) (280 mg, 2.3 mmol). Themixture was stirred for 10 minutes, and benzyl 4-hydroxy benzoate (426mg, 1.9 mmol) was added and stirred at ambient temperature for 16 hours.The mixture was diluted with ethyl acetate (100 mL) and washed withwater (10 mL), brine (10 mL), dried and solvent distilled off. The titlecompound was obtained as a pale yellow solid after chromatographicpurification.

[0942]¹H NMR (CDC₃): δ 1.42 (s, 6H), 2.05 (t, J=6.7 Hz, 2H), 2.77 (t,J=6.7 Hz, 2H), 5.37 (s, 2H), 7.25-7.50 (m, 7H), 7.58 (d, J=8.3 Hz, 1H),8.15 (d, J=8.1 Hz, 2H), 8.28 (dd, J=1.9, 8.3 Hz, 1H), 8.82 (d, J=1.9 Hz,1H).

[0943]Benzyl-4-[[5,5-dimethyl-5,6,7,8-tetrahydro-8-hydroxy-naphthalen-2-l)carbonyl]oxy]-benzoate(Compound E82)

[0944] To a solution ofbenzyl-4-[[5,5-dimethyl-5,6,7,8-tetrahydro-8-oxo-naphthalen-2-yl)carbonyl]oxyl]-benzoate((Compound E81, 377 mg, 0.88 mmol) in dimethoxyethane (20 mL) was addedsodiumborohydride (33 mg, 0.9 mmol). The mixture was stirred for 12hours at room temperature. The mixture was diluted with ethylacetate (50mL), washed with water (10 mL), brine (10 mL), dried and solventdistilled off. The tide compound was obtained as a white solid afterchromatographic purification.

[0945]¹H NMR (CDCl₃): δ 1.30 (s, 3H), 1.37 (s, 3H), 1.60-1.75 (m, 1H),1.85-2.00 (m, 2H, 2.05-2.20 (m, 1H), 230 (brs, 1H, 4.81 (t, J=5.6, 1H),5.38 (s, 2H), 7.27 (d, J=8.7 Hz, 2H), 7.35-7.51 (m, 6H), 8.04 (dd,J=1.9, 8.3 Hz, 1H), 8.15 (d, J=8.7 Hz, 2H), 8.31 (d, J=1.9 Hz).

What is claimed is:
 1. A compound of the formula

wherein X₁ is [C(R₁)₂ 9 _(n) where R₁ is independently H or alkyl of 1to 6 carbons, and n is an integer between 0 and 2; X₂ is S or O; Z is—N═N—, —N(O)═N—, —N═N(O)—, —N═CR₁—, —CR₁═N, —(CR₁═CR₁)_(n′)— where n′ isan integer having the value 0-5, —CO—NR₁—, —CS—NR₁—, —NR₁—CO, —NR₁—CS,—COO—, —OCO—; —CSO—; —OCS—; —CO—CR₁═CR₁—; R₂ is hydrogen, lower alkyl of1 to 6 carbons, F, Cl, Br, I, CF₃, fluoro substituted alkyl of 1 to 6carbons, OH, SH, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6carbons; R₃ is hydrogen, lower alkyl of 1 to 6 carbons or F; m is aninteger having the value of 0-3; o is an integer having the value of0-4; R₄ is hydrogen, alkyl of 1 to 10 carbons, alkenyl of 2 to 10carbons and having 1 to 3 double bonds, alkynyl having 2 to 10 carbonsand 1 to 3 triple bonds, carbocyclic aryl selected from the groupconsisting of phenyl, C₁-C₁₀-alkylphenyl, naphthyl,C₁-C₁₀-alkylnaphthyl, phenyl-C₁-C₁₀alkyl, napthyl-C₁-C₁₀alkyl; CN,(CH₂)_(p)CO₂H or (CH₂)_(p)CO₂R₈ where p is an integer between 0 to 10;R₅ is hydrogen, alkyl of 1 to 10 carbons, fluoro-substituted alkyl of 1to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3 doublebonds, alkynyl having 2 to 10 carbons and 1 to 3 triple bonds,carbocyclic aryl selected from the group consisting of phenyl,C₁-C₁₀-alkylphenyl, naphthyl, C₁-C₁₀-alkylnaphthyl, phenyl-C₁-C₁₀alkyl,napthyl-C₁-C₁₀alkyl; Si(C₁₋₆alkyl)₃, COR₁₄, camphanoyl,C(R₁₅)(R₁₆)X₂R₁₇; Y is a phenyl or naphthyl group, or heteroarylselected from a group consisting of pyridyl, thienyl, furyl,pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl andpyrrazolyl, said phenyl and heteroaryl groups being optionallysubstituted with one or two R₂ groups, or when Z is —(CR₁═CR₁)_(n′)— andn′ is 3, 4 or 5 then Y represents a direct valence bond between said(CR₂═CR₂)_(n′) group and B; A is (CH₂)_(q) where q is 0-5, lowerbranched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons,alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6carbons and 1 or 2 triple bonds; B is hydrogen, COOH or apharmaceutically acceptable salt thereof, COOR₈, CONR₉R₁₀, —CH₂OH,CH₂OR₁₁, CH₂OCOR₁₁, CHO, CH(OR₁₂)₂, CHOR₁₃O, —COR₇, CR₇(OR₁₂)₂,CR₇OR₁₃O, or Si(C₁₋₆alkyl)₃, where R₇ is an alkyl, cycloalkyl or alkenylgroup a containing 1 to 5 carbons, R₈ is an alkyl group of 1 to 10carbons or (trimethylsilyl)alkyl where the alkyl group has 1 to 10carbons, or a cycloalkyl group of 5 to 10 carbons, or R₈ is phenyl orlower alkylphenyl, R₉ and R₁₀ independently are hydrogen, an alkyl groupof 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl orlower alkylphenyl, R₁₁ is lower alkyl, phenyl or lower alkylphenyl, R₁₂is lower alkyl, and R₁₃ is divalent alkyl radical of 2-5 carbons; R₁₄ ishydrogen, alkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons andhaving 1 to 3 double bonds, alkynyl having 2 to 10 carbons and 1 to 3triple bonds, carbocyclic aryl selected from the group consisting ofphenyl, C₁-C₁₀-alkylphenyl, naphthyl, C₁-C₁₀-alkylnaphthyl,phenyl-C₁-C₁₀alkyl, napthyl-C₁-C₁₀alkyl, and R₁₅ and R₁₆ are hydrogen orlower alkyl of 1 to 6 carbons; R₁₇ is lower alkyl of 1 to 6 carbons, orR₁₆ and R₁₇ jointly form a ring having a total of 4 to 5 carbons and theX₂ heteroatom.
 2. A compound in accordance with claim 1 wherein Y isselected from the group consisting of phenyl, naphthyl, pyridyl, thienyland furyl.
 3. A compound in accordance with claim 2 wherein Y is phenyl.4. A compound in accordance with claim 2 wherein Y is naphthyl.
 5. Acompound in accordance with claim 1 where n is
 1. 6. A compound inaccordance with claim 1 where Z is selected from the groups consistingof —(CR₁═CR₁)_(n′)— —N═N—, —CO—CR₁═CR₁—, —COO—, and —CONH— where n′ is0, 1, or 3 with the proviso that when n′ is 3 then Y represents a directvalence bond between the —(CR₁═CR₁)_(n′)— group and the -A-B group.
 7. Acompound in accordance with claim 1 where A is (CH₂)_(q).
 8. A compoundin accordance with claim 1 where B is COOH or a pharmaceuticallyacceptable salt thereof, COOR₈, or CONR₉R₁₀.
 9. A compound of theformula

where R₁ is independently H or alkyl of 1 to 6 carbons; X₂ is S or O; Zis —N═N—, —(CR₁═CR₁)_(n′)— where n′ is an integer having the value 0-3,—CO—NH—, —COO—, —CO—CR₁═CR₁—; R₂ is hydrogen, lower alkyl of 1 to 6carbons; R₃ is hydrogen, lower alkyl of 1 to 6 carbons or F; m is aninteger having the value of 0-3; o is an integer having the value of0-4; Y is phenyl, naphthyl, pyridyl or thienyl with the proviso thatwhen n′ is 3 then Y represents a direct valence bond between the Z andA-B groups; A is (CH₂)_(q) where q is 0-5, lower branched chain alkylhaving 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2triple bonds; B is hydrogen, COOH or a pharmaceutically acceptable saltthereof, COOR₈, CONR₉R₁₀, —CH₂OH, CH₂OR₁₁, CH₂OCOR₁₁, CHO, CH(OR₁₂)₂,CHOR₁₃O, —COR₇, CR₇(OR₁₂)₂, CR₇OR₁₃O, or Si(C₁₋₆alkyl)₃, where R₇ is analkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R₈ is analkyl group of 1 to 10 carbons or (trimethylsilyl)alkyl where the alkylgroup has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, orR₈ is phenyl or lower alkylphenyl, R₉ and R₁₀ independently arehydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of5-10 carbons, or phenyl or lower alkylphenyl, R₁₁ is lower alkyl, phenylor lower alkylphenyl, R₁₂ is lower alkyl, and R₁₃ is divalent alkylradical of 2-5 carbons; R₄ is hydrogen, alkyl of 1 to 10 carbons,CH₂COOH or CH₂CO₂R₈; R₅ is hydrogen, alkyl of 1 to 10 carbons,2-tetrahydropyranyl, CH₂OCH₃ or COR₁₂.
 10. A compound in accordance withclaim 9 where Y is phenyl.
 11. A compound in accordance with claim 9where Y is naphthyl.
 12. A compound in accordance with claim 9 where Ais (CH₂)_(q) where q is 0 and where B is COOH or a pharmaceuticallyacceptable salt thereof, COOR₈, or CONR₉R₁₀.
 13. A compound inaccordance with claim 9 where R₄ is H CH₂COOH or CH₂COOR₈.
 14. Acompound in accordance with claim 9 where R₅ is H, 2-tetrahydropyranylor CH₂OCH₃.
 15. A compound of the formula

where Z is —CH═CH, C(CH₃)═CH—CH═CH—C(CH₃)═CH—, —N═N—, CO—CH═C H, CONH,or COO; Y is phenyl or when Z is (CH₃)═CH—CH═CH—C(CH₃)═CH— then Yrepresents a direct valence bond between Z and CO₂R₈, R₄ is H, CH₂COOH,CH₂COOR₈, or lower all of 1-6 carbons, R₅ is H, CH₂OCH₃, COCH₃ or2-tetrahydropyranyl, and R₈ is hydrogen or lower alkyl.
 16. A compoundin accordance with claim 15 where the Z group is connnected to the2-position of the tetrahydronaphthalene ring.
 17. A compound inaccordance with claim 15 where the Z group is connnected to the3-position of the tetrahydronaphthalene ring.
 18. A compound inaccordance with claim 17 where Z is CO—CH═CH.
 19. A compound inaccordance with claim 16 where Z is —CH═CH, C(CH₃)═CH—CH═CH—C(CH₃)═CH—,—N═N—, CONH, or COO.
 20. A compound in accordance with claim 15 where R₈is H or ethyl.